Biological Application and Disease of Oxidoreductase Enzymes

*Mezgebu Legesse Habte and Etsegenet Assefa Beyene*

#### **Abstract**

In biochemistry, oxidoreductase is a large group of enzymes that are involved in redox reaction in living organisms and in the laboratory. Oxidoreductase enzymes catalyze reaction involving oxygen insertion, hydride transfer, proton extraction, and other essential steps. There are a number of metabolic pathways like glycolysis, Krebs cycle, electron transport chain and oxidative phosphorylation, drug transformation and detoxification in liver, photosynthesis in chloroplast of plants, *etc*. that require the direct involvements of oxidoreductase enzymes. In addition, degradation of old and unnecessary endogenous biomolecules is catalyzed by a family of oxidoreductase enzymes, e.g., xanthine oxidoreductase. Oxidoreductase enzymes use NAD, FAD, or NADP as a cofactor and their efficiency, specificity, good biodegradability, and being studied well make it fit well for industrial applications. In the near future, oxidoreductase may be utilized as the best biocatalyst in pharmaceutical, food processing, and other industries. Oxidoreductase play a significant role in the field of disease diagnosis, prognosis, and treatment. By analyzing the activities of enzymes and changes of certain substances in the body fluids, the number of disease conditions can be diagnosed. Disorders resulting from deficiency (quantitative and qualitative) and excess of oxidoreductase, which may contribute to the metabolic abnormalities and decreased normal performance of life, are becoming common.

**Keywords:** biocatalyst, biological application, disease, metabolism, mutation, oxidoreductase

#### **1. Introduction**

Oxidoreductases, which includes oxidase, oxygenase, peroxidase, dehydrogenase, and others, are enzymes that catalyze redox reaction in living organisms and in the laboratory [1]. Interestingly, oxidoreductases catalyze reaction involving oxygen insertion, hydride transfer, proton extraction, and other essential steps. The substrate that is oxidized is considered as hydrogen or electron donor, whereas the substrate that is reduced during reaction as hydrogen/electrons acceptor. Most commonly, oxidoreductase enzymes use NAD, FAD, or NADP as a cofactor [2].

Organisms use this group of enzymes for synthesis of biomolecules, degradation and removal of molecules, metabolism of exogenous molecules like drugs, and so on [3–5]. Their biochemical property such as efficiency, specificity, good biodegradability, and being studied well make it fit well for industrial purposes. As a result, oxidoreductases are being utilized in nutrition, food processing, medicine, and other chemical synthesis. In the near future, oxidoreductase may be utilized as the best biocatalyst in pharmaceutical, food processing, and other industries [6, 7].

<sup>G</sup>‐3‐<sup>P</sup> <sup>þ</sup> Pi <sup>þ</sup> NADþ ! Glyceraldehyde‐3‐phosphate dehydrogenase

*Biological Application and Disease of Oxidoreductase Enzymes*

**4. Oxidoreductase in TCA cycle**

*DOI: http://dx.doi.org/10.5772/intechopen.93328*

oxidation that enter TCA cycle [19, 22].

**phosphorylation**

**5**

Pyruvate <sup>þ</sup> NADH <sup>þ</sup> <sup>H</sup>þ ! lactate dehydrogenase

A high number of NADH molecules are produced in the TCA cycle. The product

The precursor for the TCA cycle comes from lipids and carbohydrates, both of which produce the molecule acetyl-CoA. This acetyl-CoA enters the eight-step sequence of reactions that comprise the Krebs cycle, all of which occur inside mitochondria of eukaryotic cells. TCA or Krebs cycle produces NADH and FADH,

Pyruvate <sup>þ</sup> NAD<sup>þ</sup> <sup>þ</sup> CoA ! pyruvate dehydrogenase acetyl‐CoA <sup>þ</sup> NADH <sup>þ</sup> <sup>H</sup><sup>þ</sup> <sup>þ</sup> CO2

Isocitrate <sup>þ</sup> NAD<sup>þ</sup> ! isocitrate dehydrogenase alfa‐ketoglutarate <sup>þ</sup> NADH <sup>þ</sup> <sup>H</sup><sup>þ</sup> <sup>þ</sup> CO2

<sup>α</sup>‐ketoglutarate <sup>þ</sup> NAD<sup>þ</sup> <sup>þ</sup> CoA ! <sup>α</sup>‐ketoglutarate dehydrogenase succinyl CoA <sup>þ</sup> NADH

Living cells use electron transport chain to transfer electrons stepwise from substrates (NADH & FADH2) to a molecular oxygen. The proton gradient which is generated through electron transport chain runs downhill to drive the synthesis of ATP. Electron transport chain and oxidative phosphorylation take place in the matrix of mitochondria, and there are oxidoreductase enzymes impregnated in the inner mitochondrial membrane, which catalyze these reactions and are engaged in energy production. NADH:quinone oxidoreductase, also called NADH dehydrogenase (complex I), is responsible for the transfer of electrons from NADH to quinones, coupled with proton translocation across the membrane. Succinate:quinone oxidoreductase, or succinate dehydrogenase (complex II), is an enzyme of the Krebs cycle, which oxidizes succinate and reduces quinones, in the absence of proton translocation. Quilon:cytochrome c oxidoreductase (complex III), which transfers electrons from quinols to cytochrome c and cytochrome c:oxygen oxidoreductase, an aa3-type enzyme (complex IV), which receives these electrons and transfers it to oxygen are both oxidoreductase enzymes involved in electron trans-

**5. Oxidoreductase in electron transport chain and oxidative**

port chain and oxidative phosphorylation [19, 24, 25] (**Figure 1**).

Succinate <sup>þ</sup> FAD<sup>þ</sup> ! succinate dehydrogenase fumarate <sup>þ</sup> FADH2 (6)

þ CO2

of glycolysis, pyruvate, enters the TCA cycle in the form of acetyl-CoA. Except leucine and lysine, all twenty of the amino acids can be degraded to TCA cycle intermediates. And most of the fatty acids are oxidized into acetyl coA through beta

and the reactions are catalyzed by classes of oxidoreductase enzymes [23].

1, 3‐BPG <sup>þ</sup> NADH <sup>þ</sup> <sup>H</sup><sup>þ</sup>

lactate þ NAD<sup>þ</sup> (2)

(1)

(3)

(4)

(5)

Enzymes like oxidoreductase play great and significant function in the field of disease diagnosis, prognosis, and treatment [8]. By analyzing the activities of enzymes and changes of certain substances in the body fluids, a number of disease conditions can be diagnosed [9, 10]. The determination of the activity of the oxidoreductases is helpful in understanding the metabolic activity of different organs [8, 11]. For example, the activity of oxidoreductase enzymes in Krebs cycle is significantly increased during skin infection [12].

There are different disease conditions resulting from deficiency (quantitative and qualitative) and excess of oxidoreductase, which may contribute to the metabolic abnormalities and decreased normal performance of life [13, 14]. For example, relative decreases in the activities of NADH dehydrogenase and ubiquinolcytochrome c oxidoreductase are highly associated with the developments of peripheral arterial disease. Another best example is mutation of p450 oxidoreductase (POR) gene, which leads to insufficiency of P450 enzymes characterized by defective steroidogenesis. Similarly, deficiency of mitochondrial acetaldehyde dehydrogenase disturbs normal metabolism of alcohol and leads to accumulation of acetaldehyde [8, 15, 16]. These conditions in turn affect the normal development and reproduction.

#### **2. Oxidoreductase in metabolism of foodstuff**

Oxidoreductases are a family of enzymes that catalyze redox reactions. Oxidoreductases catalyze the transfer of electrons from oxidant to reductant [4]. Generally, oxidoreductases catalyze reactions which are similar to A– + B ! A+B– where A is the oxidant and B is the reductant [17]. Oxidoreductases can be oxidases where a molecular oxygen acts as an acceptor of hydrogen or electrons and dehydrogenases which are enzymes that oxidize a substrate by transferring hydrogen to an acceptor that is either NAD<sup>+</sup> /NADP<sup>+</sup> or a flavin enzyme. Other classes are oxidoreductases enzymes, peroxidases which are localized in peroxisomes and catalyze the reduction of hydrogen peroxide. Hydroxylases are involved in the addition of hydroxyl groups to their substrates, and oxygenases are key in the incorporation of oxygen from molecular oxygen into organic substrates. And reductase enzymes are involved in the catalysis of reduction reaction [2, 3, 18]. In general, oxidoreductase enzymes play an important role in both aerobic and anaerobic metabolism. They are involved in glycolysis, TCA cycle, oxidative phosphorylation, fatty acid, and amino acid metabolism [5, 19, 20].

#### **3. Oxidoreductase in glycolysis**

In glycolysis, the enzyme glyceraldehydes-3-phosphate dehydrogenase catalyzes the reduction of NAD + to NADH. In order to maintain the redox state of the cell, this NADH must be re-oxidized to NAD+, which occurs in the oxidative phosphorylation pathway [21].

$$\text{G-3-P} + \text{Pi} + \text{NAD}^+ \xleftarrow{\text{Glycerol} \cdot \text{j-phosphate} \cdot \text{dehydration}} \text{1, 3-BPG} + \text{NADH} + \text{H}^+ \tag{1}$$

Pyruvate <sup>þ</sup> NADH <sup>þ</sup> <sup>H</sup>þ ! lactate dehydrogenase lactate þ NAD<sup>þ</sup> (2)

#### **4. Oxidoreductase in TCA cycle**

Organisms use this group of enzymes for synthesis of biomolecules, degradation and removal of molecules, metabolism of exogenous molecules like drugs, and so on [3–5]. Their biochemical property such as efficiency, specificity, good biodegradability, and being studied well make it fit well for industrial purposes. As a result, oxidoreductases are being utilized in nutrition, food processing, medicine, and other chemical synthesis. In the near future, oxidoreductase may be utilized as the best biocatalyst in pharmaceutical, food processing, and other industries [6, 7]. Enzymes like oxidoreductase play great and significant function in the field of

disease diagnosis, prognosis, and treatment [8]. By analyzing the activities of enzymes and changes of certain substances in the body fluids, a number of disease conditions can be diagnosed [9, 10]. The determination of the activity of the oxidoreductases is helpful in understanding the metabolic activity of different organs [8, 11]. For example, the activity of oxidoreductase enzymes in Krebs cycle is

relative decreases in the activities of NADH dehydrogenase and ubiquinolcytochrome c oxidoreductase are highly associated with the developments of peripheral arterial disease. Another best example is mutation of p450 oxidoreductase (POR) gene, which leads to insufficiency of P450 enzymes characterized by defective steroidogenesis. Similarly, deficiency of mitochondrial acetaldehyde dehydrogenase disturbs normal metabolism of alcohol and leads to accumulation of acetaldehyde [8, 15, 16]. These conditions in turn affect the normal development

There are different disease conditions resulting from deficiency (quantitative and qualitative) and excess of oxidoreductase, which may contribute to the metabolic abnormalities and decreased normal performance of life [13, 14]. For example,

Oxidoreductases are a family of enzymes that catalyze redox reactions. Oxidoreductases catalyze the transfer of electrons from oxidant to reductant [4]. Generally, oxidoreductases catalyze reactions which are similar to A– + B ! A+B– where A is the oxidant and B is the reductant [17]. Oxidoreductases can be oxidases where a molecular oxygen acts as an acceptor of hydrogen or electrons and dehydrogenases which are enzymes that oxidize a substrate by transferring hydrogen to an

ductases enzymes, peroxidases which are localized in peroxisomes and catalyze the reduction of hydrogen peroxide. Hydroxylases are involved in the addition of hydroxyl groups to their substrates, and oxygenases are key in the incorporation of oxygen from molecular oxygen into organic substrates. And reductase enzymes are involved in the catalysis of reduction reaction [2, 3, 18]. In general, oxidoreductase enzymes play an important role in both aerobic and anaerobic metabolism. They are involved in glycolysis, TCA cycle, oxidative phosphorylation, fatty acid, and amino

In glycolysis, the enzyme glyceraldehydes-3-phosphate dehydrogenase catalyzes the reduction of NAD + to NADH. In order to maintain the redox state of the cell, this NADH must be re-oxidized to NAD+, which occurs in the oxidative phosphor-

/NADP<sup>+</sup> or a flavin enzyme. Other classes are oxidore-

significantly increased during skin infection [12].

**2. Oxidoreductase in metabolism of foodstuff**

and reproduction.

*Oxidoreductase*

acceptor that is either NAD<sup>+</sup>

acid metabolism [5, 19, 20].

ylation pathway [21].

**4**

**3. Oxidoreductase in glycolysis**

A high number of NADH molecules are produced in the TCA cycle. The product of glycolysis, pyruvate, enters the TCA cycle in the form of acetyl-CoA. Except leucine and lysine, all twenty of the amino acids can be degraded to TCA cycle intermediates. And most of the fatty acids are oxidized into acetyl coA through beta oxidation that enter TCA cycle [19, 22].

The precursor for the TCA cycle comes from lipids and carbohydrates, both of which produce the molecule acetyl-CoA. This acetyl-CoA enters the eight-step sequence of reactions that comprise the Krebs cycle, all of which occur inside mitochondria of eukaryotic cells. TCA or Krebs cycle produces NADH and FADH, and the reactions are catalyzed by classes of oxidoreductase enzymes [23].

$$\text{Pyruvate} + \text{NAD}^+ + \text{CoA} \xrightarrow{\text{pyruvate dehydrogenase}} \text{acetyl-CoA} + \text{NADH} + \text{H}^+ + \text{CO}\_2$$

$$\text{Isoscittate} + \text{NAD}^+ \xrightarrow{\text{isocittate dehydrogenase}} \text{alfa-ketoglutarate} + \text{NADH} + \text{H}^+ + \text{CO}\_2 \tag{4}$$

$$\text{\textbullet\text{-}ketoglutarate} + \text{NAD}^+ + \text{CoA} \xrightarrow{a\text{-}ketoglutarate} \begin{array}{c} \text{succinyl CoA} + \text{NADH} \\ + \text{CO}\_2 \end{array} \tag{5}$$

$$\text{Successate} + \text{FAD}^+ \xrightarrow{\text{succinate dehydrogenase}} \text{fumarate} + \text{FADH}\_2 \tag{6}$$

#### **5. Oxidoreductase in electron transport chain and oxidative phosphorylation**

Living cells use electron transport chain to transfer electrons stepwise from substrates (NADH & FADH2) to a molecular oxygen. The proton gradient which is generated through electron transport chain runs downhill to drive the synthesis of ATP. Electron transport chain and oxidative phosphorylation take place in the matrix of mitochondria, and there are oxidoreductase enzymes impregnated in the inner mitochondrial membrane, which catalyze these reactions and are engaged in energy production. NADH:quinone oxidoreductase, also called NADH dehydrogenase (complex I), is responsible for the transfer of electrons from NADH to quinones, coupled with proton translocation across the membrane. Succinate:quinone oxidoreductase, or succinate dehydrogenase (complex II), is an enzyme of the Krebs cycle, which oxidizes succinate and reduces quinones, in the absence of proton translocation. Quilon:cytochrome c oxidoreductase (complex III), which transfers electrons from quinols to cytochrome c and cytochrome c:oxygen oxidoreductase, an aa3-type enzyme (complex IV), which receives these electrons and transfers it to oxygen are both oxidoreductase enzymes involved in electron transport chain and oxidative phosphorylation [19, 24, 25] (**Figure 1**).

P450 enzymes are primarily concentrated in liver cells. The CYP2D6 isozymes play a great role in metabolizing certain opioids, neuroleptics, antidepressants, and cardiac medications. Currently it is going to be understood that difference in the genes for CYP450 enzymes play to inter-individual differences in the serum concentrations of drug metabolites, resulting in interpatient variability in drug efficacy and safety [28].

*Biological Application and Disease of Oxidoreductase Enzymes*

*DOI: http://dx.doi.org/10.5772/intechopen.93328*

**6.2 Metabolism of drugs with flavin-containing monooxygenase (FMO) system**

Flavin-containing monooxygenases (FMOs) (EC 1.14.13.8) are a family of microsomal NADPH-dependent oxidoreductase, responsible for oxygenation of nucleophilic nitrogen, sulfur, phosphorus, other drugs, and endogenous molecules. Different variants of mammalian FMOs play a significant role in the oxygenation of nucleophilic xenobiotics. FMO utilizes NADPH as a cofactor and contains one FAD as a prosthetic group. FMOs have a broad substrate specificity and their activity is maximal at or above pH 8.4. FMO is a highly abundant enzyme in the liver endoplasmic reticulum and participates in drug metabolism (activation and

Before FMOs bind to a substrate, they activate molecular oxygen. First, flavin adenine dinucleotide (FAD), the prosthetic group of FMO, is reduced by NADPH to form FADH, then oxygen is added into the FAD, and hydro-peroxide FADH-4α-OOH is produced. And then, one oxygen atom is transferred to the substrate [30, 31].

Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH) are another family of oxidoreductase responsible for metabolizing ethanol. These enzymes are highly expressed in the liver but at lower levels in many tissues and play a great role in detoxification and easy removal of alcohols. Liver is the main organ for ethanol metabolism. Oxidation of ethanol with these enzymes can become a major energy source especially in the liver, and it can interfere metabo-

The first step in ethanol metabolism is its oxidation to acetaldehyde, and this reaction is catalyzed by enzymes called alcohol dehydrogenases (ADHs). The second reaction in ethanol metabolism is oxidation of acetaldehyde into acetate catalyzed by aldehyde dehydrogenase (ALDH) enzymes. There are different ADH and ALDH enzymes encoded by different genes occurring in several alleles and enzymes that have different alcohol metabolizing capacity; thereby, they influence individuals' alcoholism risk. These are either through rapid oxidation of ethanol to acetaldehyde where there is more active ADH or slower oxidation of acetaldehyde into acetate where there are less active ALDH enzymes. Excess accumulation of acetaldehyde is toxic, which results in different adverse reactions and produces nausea, skin rash, rapid heartbeat, etc. Most commonly, single-nucleotide polymorphisms (SNPs) are responsible for ADH and ALDH gene variants, and these may occur on

Monoamine oxidase is a very important oxidoreductase enzyme mainly responsible for degradation of amine neurotransmitters like norepinephrine, epinephrine, serotonin, and dopamine. Oxidation of different endogenous and exogenous biogenic amines may produce other active or inactive metabolites. Monoamine oxidase

(MAO) is found in two isozyme forms: monoamine oxidase A (MAO-A)

both coding and non-coding regions of the gene [33, 34].

**6.4 Metabolism of drugs by monoamine oxidase (MAO)**

**6.3 Metabolism of drugs through alcohol dehydrogenase and aldehyde**

detoxification) [29].

**dehydrogenase**

lism of other nutrients [32].

**7**

**Figure 1.**

*Oxidoreductase enzymes involved in electron transport chain and oxidative phosphorylation [18].*

#### **6. Oxidoreductase in drug metabolism**

Liver is the principal organ for drug metabolism. The body uses different strategies to metabolize drugs like oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization. The main goal of drug metabolism is to make the drug more hydrophilic and excrete easily. Enzymes involved in drug metabolism are found in many tissues and organs but are more concentrated in the liver. Rates of drug metabolism may vary among individuals. Some individuals metabolize a drug so rapidly; in others, metabolism may be so slow and have different effects. Genetic factors, coexisting disorders (particularly chronic liver disorders and advanced heart failure), and drug interactions are responsible factors for variation of rate of drug metabolism among individuals [26].

Generally, drug metabolism can be in three phases. In phase I drug metabolism, oxidoreductase enzymes such as cytochrome P450 oxidases add polar or reactive groups into drugs (xenobiotics). In phase I reaction, drugs are introduced into new or modified functional group through oxidation, reduction, and hydrolysis. In Phase II reactions, modified compounds are in conjugation with an endogenous substance, e.g., glucuronic acid, sulfate, and glycine. Phase II reactions are synthetic, and compounds become more polar and thus, more readily excreted by the kidneys (in urine) and the liver (in bile) than those formed in nonsynthetic reactions. At the end, in phase III reaction, the conjugated drugs (xenobiotics) may be further processed, before being recognized by efflux transporters and pumped out of cells. The metabolism of drug often converts hydrophobic compounds into hydrophilic products that are more readily excreted [27].

In normal cases, human body wants to remove or detoxify any compounds that cannot be metabolized otherwise utilized to serve the needs of the body. This removal process is carried out mainly by the liver. The liver has classes of oxidoreductase enzymes that are extremely effective at detoxification and removal of drugs from the body [5, 18].

#### **6.1 Metabolism of drugs through cytochrome P450 monooxygenase**

Oxidation and metabolism of a high number of drugs and endogenous molecules are catalyzed by a class of oxidoreductase enzymes called cytochrome P450 monooxygenases. Even though they are distributed throughout the body, cytochrome P450 enzymes are primarily concentrated in liver cells. The CYP2D6 isozymes play a great role in metabolizing certain opioids, neuroleptics, antidepressants, and cardiac medications. Currently it is going to be understood that difference in the genes for CYP450 enzymes play to inter-individual differences in the serum concentrations of drug metabolites, resulting in interpatient variability in drug efficacy and safety [28].

#### **6.2 Metabolism of drugs with flavin-containing monooxygenase (FMO) system**

Flavin-containing monooxygenases (FMOs) (EC 1.14.13.8) are a family of microsomal NADPH-dependent oxidoreductase, responsible for oxygenation of nucleophilic nitrogen, sulfur, phosphorus, other drugs, and endogenous molecules. Different variants of mammalian FMOs play a significant role in the oxygenation of nucleophilic xenobiotics. FMO utilizes NADPH as a cofactor and contains one FAD as a prosthetic group. FMOs have a broad substrate specificity and their activity is maximal at or above pH 8.4. FMO is a highly abundant enzyme in the liver endoplasmic reticulum and participates in drug metabolism (activation and detoxification) [29].

Before FMOs bind to a substrate, they activate molecular oxygen. First, flavin adenine dinucleotide (FAD), the prosthetic group of FMO, is reduced by NADPH to form FADH, then oxygen is added into the FAD, and hydro-peroxide FADH-4α-OOH is produced. And then, one oxygen atom is transferred to the substrate [30, 31].

#### **6.3 Metabolism of drugs through alcohol dehydrogenase and aldehyde dehydrogenase**

Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH) are another family of oxidoreductase responsible for metabolizing ethanol. These enzymes are highly expressed in the liver but at lower levels in many tissues and play a great role in detoxification and easy removal of alcohols. Liver is the main organ for ethanol metabolism. Oxidation of ethanol with these enzymes can become a major energy source especially in the liver, and it can interfere metabolism of other nutrients [32].

The first step in ethanol metabolism is its oxidation to acetaldehyde, and this reaction is catalyzed by enzymes called alcohol dehydrogenases (ADHs). The second reaction in ethanol metabolism is oxidation of acetaldehyde into acetate catalyzed by aldehyde dehydrogenase (ALDH) enzymes. There are different ADH and ALDH enzymes encoded by different genes occurring in several alleles and enzymes that have different alcohol metabolizing capacity; thereby, they influence individuals' alcoholism risk. These are either through rapid oxidation of ethanol to acetaldehyde where there is more active ADH or slower oxidation of acetaldehyde into acetate where there are less active ALDH enzymes. Excess accumulation of acetaldehyde is toxic, which results in different adverse reactions and produces nausea, skin rash, rapid heartbeat, etc. Most commonly, single-nucleotide polymorphisms (SNPs) are responsible for ADH and ALDH gene variants, and these may occur on both coding and non-coding regions of the gene [33, 34].

#### **6.4 Metabolism of drugs by monoamine oxidase (MAO)**

Monoamine oxidase is a very important oxidoreductase enzyme mainly responsible for degradation of amine neurotransmitters like norepinephrine, epinephrine, serotonin, and dopamine. Oxidation of different endogenous and exogenous biogenic amines may produce other active or inactive metabolites. Monoamine oxidase (MAO) is found in two isozyme forms: monoamine oxidase A (MAO-A)

**6. Oxidoreductase in drug metabolism**

**Figure 1.**

*Oxidoreductase*

ation of rate of drug metabolism among individuals [26].

products that are more readily excreted [27].

from the body [5, 18].

**6**

Liver is the principal organ for drug metabolism. The body uses different strategies to metabolize drugs like oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization. The main goal of drug metabolism is to make the drug more hydrophilic and excrete easily. Enzymes involved in drug metabolism are found in many tissues and organs but are more concentrated in the liver. Rates of drug metabolism may vary among individuals. Some individuals metabolize a drug so rapidly; in others, metabolism may be so slow and have different effects. Genetic factors, coexisting disorders (particularly chronic liver disorders and advanced heart failure), and drug interactions are responsible factors for vari-

*Oxidoreductase enzymes involved in electron transport chain and oxidative phosphorylation [18].*

Generally, drug metabolism can be in three phases. In phase I drug metabolism, oxidoreductase enzymes such as cytochrome P450 oxidases add polar or reactive groups into drugs (xenobiotics). In phase I reaction, drugs are introduced into new or modified functional group through oxidation, reduction, and hydrolysis. In Phase II reactions, modified compounds are in conjugation with an endogenous substance, e.g., glucuronic acid, sulfate, and glycine. Phase II reactions are synthetic, and compounds become more polar and thus, more readily excreted by the kidneys (in urine) and the liver (in bile) than those formed in nonsynthetic reactions. At the end, in phase III reaction, the conjugated drugs (xenobiotics) may be further processed, before being recognized by efflux transporters and pumped out of cells. The metabolism of drug often converts hydrophobic compounds into hydrophilic

In normal cases, human body wants to remove or detoxify any compounds that

Oxidation and metabolism of a high number of drugs and endogenous molecules

monooxygenases. Even though they are distributed throughout the body, cytochrome

cannot be metabolized otherwise utilized to serve the needs of the body. This removal process is carried out mainly by the liver. The liver has classes of oxidoreductase enzymes that are extremely effective at detoxification and removal of drugs

**6.1 Metabolism of drugs through cytochrome P450 monooxygenase**

are catalyzed by a class of oxidoreductase enzymes called cytochrome P450

preferentially deaminates serotonin, norepinephrine, epinephrine, and dietary vasopressors such as tyramine, and MAO-B preferentially deaminates dopamine and phenethylamine. They are integral flavoproteins components of outer mitochondrial membranes in neurons and glia cell. The two isozymes of MAO differ based on substrate specificity and sensitivity to different inhibitors [35].

different redox-active centers for doing their functions. These unique features of oxidoreductase enzymes make it valuable targets of pharmaceutical and chemical industries. Advancement in recombinant DNA technology, protein engineering, and bioinformatics is a critical event in the application of enzymes in different industries. A number of dug synthesis processes require the involvement of oxido-

An oxidoreductase is involved in the synthesis of 3,4-dihydroxylphenyl alanine

Enzymes are biological catalysts and have a number of applications in agricultural fields. Using enzymes has great efficacy and efficiency over chemical catalysts with respect to their productivity, time, cost, quality, and quantity products. There are different classes of oxidoreductase enzymes nowadays involved in fertilizer production, dairy processing, and other food processing in agricultural sector, and their cost-effectiveness and quality product were confirmed by a number of

Manipulation of gene cod for different oxidoreductase in plants can also change the characters of plants in a way that it increases productivity and resists adverse effects of herbicide and environmental changes. For example, modification of DNA for glyphosate oxidoreductase (GOX) enzyme that catalyzes the oxidative cleavage of the CdN bond on the carboxyl side of glyphosate, resulting in the formation of aminomethylphosphonic acid (AMPA) and glyoxylate thereby augmented expression of GOX plants, results in glyphosate herbicide side effect tolerance [46, 47]. Some families of oxidoreductase like xanthine dehydrogenase in plants are used to metabolize reactive oxygen species associated with plant-pathogen and protect plants from stress-induced oxidative damage. Upregulation of xanthine dehydroge-

Classes of oxidoreductase are also involved in dairy processing. Glucose oxidase produced by fungal species acts as preservatives in dairy products and other foods. The intermediate and end product of glucose oxidase have antimicrobial effect [50]. Isozyme of xanthine oxidoreductase in bovine milk, which catalyzes reduction of oxygen to generate reactive metabolite is used as an anti-microbial agent in the neonatal gastrointestinal tract [51]. Similarly, peroxidases which are a family of oxidoreductase found in higher plants catalyze the oxidation of many compounds including phenolics, in the presence of hydrogen peroxide responsible in browning or darkening of noodles and pasta and associated with a grain quality defect [52]. Protochlorophyllide oxidoreductase (POR), which exists in two isozymes POR A and POR B, plays a vital role in plant chlorophyll synthesis, and manipulation on these genes can induce plant development [53]. In general, there are a number of

nase expression in plants is helpful to increase productivity [48, 49].

(DOPA), and 3,4-dihydroxylphenyl alanine is a drug used for treatment of Parkinson's disease [41]. Similarly, a class of oxidoreductase called monoamine oxidase (MAO) catalyzes enantiomeric desymmetrization of bicyclic proline intermediate, which is an important precursor in the synthesis of boceprevir. Boceprevir is a NS3 protease inhibitor that is used for the treatment of chronic hepatitis C infections. Using MAO in this reaction reduces time and waste product generation and is economically cost-competitive and profitable [42]. Its coenzyme specificity makes oxidoreductase an effective biocatalyst in protein engineering [43]. In vitro different oxidoreductase enzymes are involved in regeneration of coenzymes, pyridine nucleotides, NAD(H) and NADP(H). Alcohol dehydrogenase and format dehydrogenase are frequently used enzymes for recycling of coenzymes, and the intermediate products are useful in the synthesis of pharmaceutical drugs such as

reductase enzymes [6].

mevinic acid [44, 45].

researches [3].

**9**

**7.2 Oxidoreductase enzymes in agricultural sector**

*Biological Application and Disease of Oxidoreductase Enzymes*

*DOI: http://dx.doi.org/10.5772/intechopen.93328*

Monoamine oxidase enzymes catalyze the primary catabolic pathway for 5-HT oxidative deamination. Serotonin is converted into 5-hydroxy-indoleacetaldehyde, and this product is further oxidized by a NAD-dependent aldehyde dehydrogenase to form 5-hydroxyindoleacetic acid (5-HIAA). Immunohistochemical techniques and in situ hybridization histochemistry techniques are used to study the neuroanatomical localization and biochemical nature of the two forms of MAO [36].

Different antidepressant drugs like phenelzine and tranylcypromine inhibit the activity of monoamine oxidase. These are a result of MAO metabolizes biogenic amines such as 5-HT, DA, and NE. In addition, different dopaminergic neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are metabolized by MAO [37].

#### **6.5 NADPH-cytochrome P450 reductase (CPR) in drug metabolism**

Another essential class of oxidoreductase enzyme is NADPH-cytochrome P450 reductase (CPR). It is a membrane-bound protein localized in the ER membrane. PR involves in the detoxification and activation of a number of xenobiotics. CPR uses FAD and FMN as cofactors, and it transfers the hydride ion of NADPH to FAD, and then FAD transfers electrons to FMN and other oxidases. Finally, it reduces the P450 enzyme heme center to activate molecular oxygen. Thus, electrons transfer from NADPH to the P450 heme center by CPR, which is central for P450-catalyzed metabolism. Flow of electron can be expressed as follows:

$$\text{NADPH} \rightarrow \text{FAD} \rightarrow \text{FMN} \rightarrow \text{P450} \rightarrow \text{O}\_2 \tag{7}$$

Human cytochrome P450 reductase is encoded by the POR gene. It is a 78-kDa multi domain diflavin reductase that binds both FMN and FAD and is attached to the cytoplasmic side of the endoplasmic reticulum via a transmembrane segment at its N-terminus [5, 15, 38].

#### **7. Industrial application of oxidoreductase enzymes**

Several industries such as pharmaceutical, foods, biofuel production, natural gas conversion, and others have used enzyme catalysis at commercial scale [39]. Classes of oxidoreductase enzymes are becoming a target by a number of industries. The family of oxidoreductase like heme-containing peroxidases and peroxygenases, flavin-containing oxidases and dehydrogenases, and different copper-containing oxidoreductases is involved in synthesis and degradation of interested products by the above industries and they are biocatalysts of interest for establishing a bio-based economy. Oxidoreductase enzymes have the highest potential in the production of polymer building blocks, sustainable chemicals, and materials from plant biomass within lignocellulose biorefineries [6, 7, 40].

#### **7.1 Oxidoreductase enzymes in pharmaceutical industries**

Enzymes are biological catalysts and have great specificity, efficiency, and selectivity in the reaction they catalyze [39]. Oxidoreductase enzymes have

*Biological Application and Disease of Oxidoreductase Enzymes DOI: http://dx.doi.org/10.5772/intechopen.93328*

preferentially deaminates serotonin, norepinephrine, epinephrine, and dietary vasopressors such as tyramine, and MAO-B preferentially deaminates dopamine and phenethylamine. They are integral flavoproteins components of outer mitochondrial membranes in neurons and glia cell. The two isozymes of MAO differ

Monoamine oxidase enzymes catalyze the primary catabolic pathway for 5-HT oxidative deamination. Serotonin is converted into 5-hydroxy-indoleacetaldehyde, and this product is further oxidized by a NAD-dependent aldehyde dehydrogenase to form 5-hydroxyindoleacetic acid (5-HIAA). Immunohistochemical techniques and in situ hybridization histochemistry techniques are used to study the neuroanatomical localization and biochemical nature of the two forms of MAO [36].

Different antidepressant drugs like phenelzine and tranylcypromine inhibit the activity of monoamine oxidase. These are a result of MAO metabolizes biogenic amines such as 5-HT, DA, and NE. In addition, different dopaminergic neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are metabolized by

Another essential class of oxidoreductase enzyme is NADPH-cytochrome P450 reductase (CPR). It is a membrane-bound protein localized in the ER membrane. PR involves in the detoxification and activation of a number of xenobiotics. CPR uses FAD and FMN as cofactors, and it transfers the hydride ion of NADPH to FAD, and then FAD transfers electrons to FMN and other oxidases. Finally, it reduces the P450 enzyme heme center to activate molecular oxygen. Thus, electrons transfer from NADPH to the P450 heme center by CPR, which is central for P450-catalyzed

Human cytochrome P450 reductase is encoded by the POR gene. It is a 78-kDa multi domain diflavin reductase that binds both FMN and FAD and is attached to the cytoplasmic side of the endoplasmic reticulum via a transmembrane segment at

Several industries such as pharmaceutical, foods, biofuel production, natural gas conversion, and others have used enzyme catalysis at commercial scale [39]. Classes of oxidoreductase enzymes are becoming a target by a number of industries. The family of oxidoreductase like heme-containing peroxidases and peroxygenases, flavin-containing oxidases and dehydrogenases, and different copper-containing oxidoreductases is involved in synthesis and degradation of interested products by the above industries and they are biocatalysts of interest for establishing a bio-based economy. Oxidoreductase enzymes have the highest potential in the production of polymer building blocks, sustainable chemicals, and materials from plant biomass

Enzymes are biological catalysts and have great specificity, efficiency, and selectivity in the reaction they catalyze [39]. Oxidoreductase enzymes have

NADPH ! FAD ! FMN ! P450 ! O2 (7)

based on substrate specificity and sensitivity to different inhibitors [35].

**6.5 NADPH-cytochrome P450 reductase (CPR) in drug metabolism**

metabolism. Flow of electron can be expressed as follows:

**7. Industrial application of oxidoreductase enzymes**

**7.1 Oxidoreductase enzymes in pharmaceutical industries**

within lignocellulose biorefineries [6, 7, 40].

MAO [37].

*Oxidoreductase*

its N-terminus [5, 15, 38].

**8**

different redox-active centers for doing their functions. These unique features of oxidoreductase enzymes make it valuable targets of pharmaceutical and chemical industries. Advancement in recombinant DNA technology, protein engineering, and bioinformatics is a critical event in the application of enzymes in different industries. A number of dug synthesis processes require the involvement of oxidoreductase enzymes [6].

An oxidoreductase is involved in the synthesis of 3,4-dihydroxylphenyl alanine (DOPA), and 3,4-dihydroxylphenyl alanine is a drug used for treatment of Parkinson's disease [41]. Similarly, a class of oxidoreductase called monoamine oxidase (MAO) catalyzes enantiomeric desymmetrization of bicyclic proline intermediate, which is an important precursor in the synthesis of boceprevir. Boceprevir is a NS3 protease inhibitor that is used for the treatment of chronic hepatitis C infections. Using MAO in this reaction reduces time and waste product generation and is economically cost-competitive and profitable [42]. Its coenzyme specificity makes oxidoreductase an effective biocatalyst in protein engineering [43]. In vitro different oxidoreductase enzymes are involved in regeneration of coenzymes, pyridine nucleotides, NAD(H) and NADP(H). Alcohol dehydrogenase and format dehydrogenase are frequently used enzymes for recycling of coenzymes, and the intermediate products are useful in the synthesis of pharmaceutical drugs such as mevinic acid [44, 45].

#### **7.2 Oxidoreductase enzymes in agricultural sector**

Enzymes are biological catalysts and have a number of applications in agricultural fields. Using enzymes has great efficacy and efficiency over chemical catalysts with respect to their productivity, time, cost, quality, and quantity products. There are different classes of oxidoreductase enzymes nowadays involved in fertilizer production, dairy processing, and other food processing in agricultural sector, and their cost-effectiveness and quality product were confirmed by a number of researches [3].

Manipulation of gene cod for different oxidoreductase in plants can also change the characters of plants in a way that it increases productivity and resists adverse effects of herbicide and environmental changes. For example, modification of DNA for glyphosate oxidoreductase (GOX) enzyme that catalyzes the oxidative cleavage of the CdN bond on the carboxyl side of glyphosate, resulting in the formation of aminomethylphosphonic acid (AMPA) and glyoxylate thereby augmented expression of GOX plants, results in glyphosate herbicide side effect tolerance [46, 47]. Some families of oxidoreductase like xanthine dehydrogenase in plants are used to metabolize reactive oxygen species associated with plant-pathogen and protect plants from stress-induced oxidative damage. Upregulation of xanthine dehydrogenase expression in plants is helpful to increase productivity [48, 49].

Classes of oxidoreductase are also involved in dairy processing. Glucose oxidase produced by fungal species acts as preservatives in dairy products and other foods. The intermediate and end product of glucose oxidase have antimicrobial effect [50]. Isozyme of xanthine oxidoreductase in bovine milk, which catalyzes reduction of oxygen to generate reactive metabolite is used as an anti-microbial agent in the neonatal gastrointestinal tract [51]. Similarly, peroxidases which are a family of oxidoreductase found in higher plants catalyze the oxidation of many compounds including phenolics, in the presence of hydrogen peroxide responsible in browning or darkening of noodles and pasta and associated with a grain quality defect [52]. Protochlorophyllide oxidoreductase (POR), which exists in two isozymes POR A and POR B, plays a vital role in plant chlorophyll synthesis, and manipulation on these genes can induce plant development [53]. In general, there are a number of

#### *Oxidoreductase*

oxidoreductase enzymes found in plants, and their normal activity is crucial for qualitative and quantitative productivity of crops, and these were confirmed by a number of active researches. Different interventions are also going on at gene level to control the expression of oxidoreductase enzymes in plant as needed [3].

recycling of NADH to NAD<sup>+</sup>

*DOI: http://dx.doi.org/10.5772/intechopen.93328*

*Biological Application and Disease of Oxidoreductase Enzymes*

metabolism of the above macromolecules [60].

ous clinical problem like atherosclerosis [62, 63].

Both authors read and approved the final manuscript.

[57, 58].

failure [61].

**Conflict of interests**

**Authors' contributions**

**11**

, and in turn, this is essential to sustain Krebs cycle and

glycolysis. Mutations in both nuclear and mitochondrial DNA for Complex I gene are responsible for mitochondrial disease. Individuals with mitochondrial diseases suffer from an energy insufficiency characterized by myopathies, neuropathy, delayed development, cardiomyopathy, lactic acidosis, and others. Furthermore, since mitochondria are a hub of metabolism, mitochondrial dysfunctions are highly associated with metabolic diseases like hypertension, obesity, diabetes, neurodegenerative diseases, and even aging. Deficiency of complex I leads to elevation of NADH levels in the mitochondria that inhibit pyruvate dehydrogenase and αketoglutarate dehydrogenase. This condition completely inhibits Krebs cycle, and it is measured by CO2 evolution from [14C] labeled precursors. Similarly, complex II (succinate:ubiquinone oxidoreductase) deficiency affects both fatty acid oxidation and electron transport chain, and it induces retinopathies and encephalopathies

Deficiency of the pyruvate dehydrogenase complex (PDHC), another class of oxidoreductase enzymes, causes similar clinical and biochemical alteration in energy production with complex I (NADH-CoQ oxidoreductase) [59]. Both TCA cycle and respiratory chain can be affected by succinate dehydrogenase deficiency. Deficiency of oxidoreductase enzymes involved in Krebs cycle affects all carbohydrate, protein, fat, and nucleic acid metabolism as it is a common pathway for

Oxidoreductase enzymes are also involved in bile acid synthesis. Classes of oxidoreductase enzymes called 3beta-hydroxy-Delta (5)-C (27)-steroid oxidoreductase catalyze an early step of bile acids synthesis from cholesterol and are encoded by HSD3B7 gene on chromosome 16p11.2-12. Mutations of HSD3B7 gene affect bile acids synthesis, cause development of progressive liver disease characterized by cholestatic jaundice, malabsorption of lipids, and lipid-soluble vitamins from the gastrointestinal tract, and finally progress to cirrhosis and liver

One important biomolecule that acts as a precursor for other molecules and a component of cell membrane is cholesterol. Mammalian cells can get cholesterol from de novo biosynthesis or uptake of exogenously derived cholesterol associated

with plasma low-density lipoprotein (LDL). 3-Hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, which is a class of oxidoreductase, catalyzes the rate-limiting steps of de novo cholesterol biosynthetic pathway and target for manipulation pharmacologically. Under or over activity of HMG-CoA reductase can

disturb cholesterol homeostasis and lead to either hypercholesterolemia or

The authors declare that they have no competing interests.

hypocholesterolemia. And disturbed cholesterol level associated with number seri-

Mezgeu Legesse Habte drafted the paper and write the literature review.

Etsegenet Assefa assisted in guidance, critical assessment and peer review of the writing. Both authors have given their final approval of this version to be published.

#### **8. Disease related with oxidoreductase enzyme disorder**

Oxidoreductase enzymes are involved in a number of valuable biochemical reactions in the living organism, and their qualitative and quantitative normality is essential. For example, one important class of oxidoreductase is xanthine oxidoreductase (XOR) that catalyzes oxidative hydroxylation of hypoxanthine to xanthine then to uric acid and over activity XOR leads to hyperuricemia and concomitant production of reactive oxygen species. In turn, hyperuricemia is confirmed as an independent risk factor for a number of clinical conditions such as gout, cardiovascular disease, hypertension, and others. Different urate-lowering drugs or XOR inhibitors are nowadays implemented to prevent and manage hyperuricemia disorder [9].

Another important class of oxidoreductase enzyme is cytochrome P450 oxidoreductase (POR) that is essential for multiple metabolic processes. Cytochrome P450 enzymes are involved in metabolism of steroid hormones, drugs, and xenobiotics. Nowadays, more than 200 different mutations and polymorphisms in POR gene have been identified and cause a complex set of disorders. Deficiency of cytochrome P450 oxidoreductase affects normal production of hormone; specifically, it affects steroid hormones, which are needed for normal development and reproduction. This is highly linked with the reproductive system, skeletal system, and other functions. Signs and symptoms can be seen from birth to adult age with different severities. Individuals with moderate cytochrome P450 oxidoreductase deficiency may have ambiguous external genitalia and have a high chance of infertility but a normal skeletal structure [5, 16, 18].

Aldehyde dehydrogenase 2 (ALDH2) deficiency known as Asian glow or alcohol flushing syndrome is a common genetic health problem that interferes with alcohol metabolism, and ALDH2 is a classical family of oxidoreductase enzymes. It was confirmed that ALDH2 deficiency results in the accumulation acetaldehyde, which is a toxic metabolite of alcohol metabolism and responsible for a number of health challenges like esophageal, head, and neck cancer. A number of researches conclude that acetaldehyde is a group 1 carcinogenic metabolite [33, 54]. Similarly, monoamine oxidase deficiency, which is a family oxidoreductase enzyme, affects the normal metabolism of serotonin and catecholamines. It is a rare X-linked disorder characterized by mild intellectual disability, and behavioral challenges appear at earlier age. Monoamine oxidase-A deficiency that occurs almost exclusively in males has episodes of skin flushing, excessive sweating, headaches, and diarrhea. Monoamine oxidase-A deficiency can be diagnosed by finding an elevated urinary concentration of the monoamine oxidase-A substrates in combination with reduced amounts of the monoamine oxidase products [36, 55].

Mitochondria generate huge amounts of energy (ATP) to eukaryotic cells through oxidation of fats and sugars; and fatty acid β-oxidation and oxidative phosphorylation are two metabolic pathways that are central to this process. Qualitative and quantitative normality of oxidoreductase enzymes involved in oxidative phosphorylation and fatty acid oxidations are essential to get sufficient energy (ATP) form metabolism. Deficiency of a complex I (NADH-CoQ oxidoreductase) is common, and a well-characterized mitochondrial problem causes reduced ATP production [56]. Complex I (NADH-CoQ oxidoreductase) is responsible for

oxidoreductase enzymes found in plants, and their normal activity is crucial for qualitative and quantitative productivity of crops, and these were confirmed by a number of active researches. Different interventions are also going on at gene level

Oxidoreductase enzymes are involved in a number of valuable biochemical reactions in the living organism, and their qualitative and quantitative normality is essential. For example, one important class of oxidoreductase is xanthine oxidoreductase (XOR) that catalyzes oxidative hydroxylation of hypoxanthine to xanthine then to uric acid and over activity XOR leads to hyperuricemia and concomitant production of reactive oxygen species. In turn, hyperuricemia is confirmed as an independent risk factor for a number of clinical conditions such as gout, cardiovascular disease, hypertension, and others. Different urate-lowering drugs or XOR inhibitors are nowadays implemented to prevent and manage hyperuricemia

Another important class of oxidoreductase enzyme is cytochrome P450 oxidoreductase (POR) that is essential for multiple metabolic processes. Cytochrome P450 enzymes are involved in metabolism of steroid hormones, drugs, and xenobiotics. Nowadays, more than 200 different mutations and polymorphisms in POR gene have been identified and cause a complex set of disorders. Deficiency of cytochrome P450 oxidoreductase affects normal production of hormone; specifically, it affects steroid hormones, which are needed for normal development and reproduction. This is highly linked with the reproductive system, skeletal system, and other functions. Signs and symptoms can be seen from birth to adult age with different severities. Individuals with moderate cytochrome P450 oxidoreductase deficiency may have ambiguous external genitalia and have a high chance of infer-

Aldehyde dehydrogenase 2 (ALDH2) deficiency known as Asian glow or alcohol flushing syndrome is a common genetic health problem that interferes with alcohol metabolism, and ALDH2 is a classical family of oxidoreductase enzymes. It was confirmed that ALDH2 deficiency results in the accumulation acetaldehyde, which is a toxic metabolite of alcohol metabolism and responsible for a number of health challenges like esophageal, head, and neck cancer. A number of researches conclude that acetaldehyde is a group 1 carcinogenic metabolite [33, 54]. Similarly, monoamine oxidase deficiency, which is a family oxidoreductase enzyme, affects the normal metabolism of serotonin and catecholamines. It is a rare X-linked disorder characterized by mild intellectual disability, and behavioral challenges appear at earlier age. Monoamine oxidase-A deficiency that occurs almost exclusively in males has episodes of skin flushing, excessive sweating, headaches, and diarrhea. Monoamine oxidase-A deficiency can be diagnosed by finding an elevated urinary concentration of the monoamine oxidase-A substrates in combination with reduced

Mitochondria generate huge amounts of energy (ATP) to eukaryotic cells through oxidation of fats and sugars; and fatty acid β-oxidation and oxidative phosphorylation are two metabolic pathways that are central to this process. Qualitative and quantitative normality of oxidoreductase enzymes involved in oxidative phosphorylation and fatty acid oxidations are essential to get sufficient energy (ATP) form metabolism. Deficiency of a complex I (NADH-CoQ oxidoreductase) is common, and a well-characterized mitochondrial problem causes reduced ATP production [56]. Complex I (NADH-CoQ oxidoreductase) is responsible for

to control the expression of oxidoreductase enzymes in plant as needed [3].

**8. Disease related with oxidoreductase enzyme disorder**

tility but a normal skeletal structure [5, 16, 18].

amounts of the monoamine oxidase products [36, 55].

disorder [9].

*Oxidoreductase*

**10**

recycling of NADH to NAD<sup>+</sup> , and in turn, this is essential to sustain Krebs cycle and glycolysis. Mutations in both nuclear and mitochondrial DNA for Complex I gene are responsible for mitochondrial disease. Individuals with mitochondrial diseases suffer from an energy insufficiency characterized by myopathies, neuropathy, delayed development, cardiomyopathy, lactic acidosis, and others. Furthermore, since mitochondria are a hub of metabolism, mitochondrial dysfunctions are highly associated with metabolic diseases like hypertension, obesity, diabetes, neurodegenerative diseases, and even aging. Deficiency of complex I leads to elevation of NADH levels in the mitochondria that inhibit pyruvate dehydrogenase and αketoglutarate dehydrogenase. This condition completely inhibits Krebs cycle, and it is measured by CO2 evolution from [14C] labeled precursors. Similarly, complex II (succinate:ubiquinone oxidoreductase) deficiency affects both fatty acid oxidation and electron transport chain, and it induces retinopathies and encephalopathies [57, 58].

Deficiency of the pyruvate dehydrogenase complex (PDHC), another class of oxidoreductase enzymes, causes similar clinical and biochemical alteration in energy production with complex I (NADH-CoQ oxidoreductase) [59]. Both TCA cycle and respiratory chain can be affected by succinate dehydrogenase deficiency. Deficiency of oxidoreductase enzymes involved in Krebs cycle affects all carbohydrate, protein, fat, and nucleic acid metabolism as it is a common pathway for metabolism of the above macromolecules [60].

Oxidoreductase enzymes are also involved in bile acid synthesis. Classes of oxidoreductase enzymes called 3beta-hydroxy-Delta (5)-C (27)-steroid oxidoreductase catalyze an early step of bile acids synthesis from cholesterol and are encoded by HSD3B7 gene on chromosome 16p11.2-12. Mutations of HSD3B7 gene affect bile acids synthesis, cause development of progressive liver disease characterized by cholestatic jaundice, malabsorption of lipids, and lipid-soluble vitamins from the gastrointestinal tract, and finally progress to cirrhosis and liver failure [61].

One important biomolecule that acts as a precursor for other molecules and a component of cell membrane is cholesterol. Mammalian cells can get cholesterol from de novo biosynthesis or uptake of exogenously derived cholesterol associated with plasma low-density lipoprotein (LDL). 3-Hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, which is a class of oxidoreductase, catalyzes the rate-limiting steps of de novo cholesterol biosynthetic pathway and target for manipulation pharmacologically. Under or over activity of HMG-CoA reductase can disturb cholesterol homeostasis and lead to either hypercholesterolemia or hypocholesterolemia. And disturbed cholesterol level associated with number serious clinical problem like atherosclerosis [62, 63].

#### **Conflict of interests**

The authors declare that they have no competing interests.

#### **Authors' contributions**

Mezgeu Legesse Habte drafted the paper and write the literature review.

Etsegenet Assefa assisted in guidance, critical assessment and peer review of the writing. Both authors have given their final approval of this version to be published. Both authors read and approved the final manuscript.

### **Ethical statement**

**Availability of data and material:** All necessary data and materials related to the article are included in the article**.**

**References**

[1] Trisolini L, Gambacorta N, Gorgoglion R, et al. FAD/NADH dependent oxidoreductases: From different amino acid sequences to similar protein shapes for playing an ancient function. Journal of Clinical

[2] McDonald A. The Enzyme List Class 1—Oxidoreductases. Nomenclature Committee of the International Union of Biochemistry and Molecular Biology

*Biological Application and Disease of Oxidoreductase Enzymes*

*DOI: http://dx.doi.org/10.5772/intechopen.93328*

Journal of Physiology. 2004;**555**(3):

Hyperuricemia and XOR inhibitors. Medical Science Monitor. 2016;**22**:

[10] Raja MMM, Raja A, Imran MM, Santha AMI, Devasena K. Enzyme application in diagnostic application. Biotechnology. 2011;**10**(1):51-59

[11] Hoidal JR, Xu R, Huecksteadt T, Sanders KA, Pfeffer K, Sturrock AB. Lung injury and oxidoreductases. Environmental Health Perspectives.

[12] Uravleva GF. Histochemical investigation of the activity of oxidoreductases in the skin lesions of lepromatous leprosy patients. Bulletin of the World Health Organization. 1972;

[13] Pey AL, Megarity CF, Timson DJ. NAD(P)H quinone oxidoreductase (NQO1): An enzyme which needs just enough mobility, in just the right places.

[14] Brass EP, Hiatt WR, Gardner AW,

dehydrogenase and ubiquinolcytochrome c oxidoreductase in peripheral arterial disease. American Journal of Physiology. Heart and Circulatory Physiology. 2001;

[15] Fang Y, Gao N, Tian X, Zhou J, et al.

[16] Flück CE, Tajima T, Pandey AV, et al. Mutant P450 oxidoreductase

Bioscience Reports. 2019;**39**(1)

Hoppe CL. Decreased NADH

Effect of P450 oxidoreductase polymorphisms on the metabolic activities of ten cytochrome P450s varied by polymorphic CYP genotypes in human liver microsomes. Cellular Physiology and Biochemistry. 2018;**47**:

**280**:H603-H609

1604-1616

1998;**106**(5):1235-1239

**46**:813-819

[9] Chen C, Lü J-M, Yao Q.

589-606

2501-2512

[3] Gramss G, Rudeschko O. Activities of oxidoreductase enzymes in tissue extracts and sterile root exudates of three crop plants, and some properties of the peroxidase component. New Phytology. 1998;**138**:401-409

[4] Braune A, Gütschow M, Blau M. An NADH-dependent reductase from *Eubacterium ramulus* catalyzes the stereospecific heteroring cleavage of flavanones and flavanonols. Applied and Environmental Microbiology. 2019. DOI: 10.1128/AEM.01233-19

[5] Rendic S, Guengerich FP. Survey of human oxidoreductases and cytochrome

[6] Martíneza AT, Ruiz-Dueñasa FJ, Camareroa S, et al. Oxidoreductases on

biotransformations. Biotechnology

[7] Chapman J, Ismail AE, Dinu CZ. Industrial applications of enzymes: Recent advances, techniques, and outlooks. Catalysts. 2018;**8**:238

[8] Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: Molecular mechanisms and pathophysiological implications. The

their way to industrial

**13**

Advances. 2017;**35**:815-831

P450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chemical Research in Toxicology. 2015;**28**:38-42

Medicine. 2019;**8**:2117

(NC-IUBMB); 2019

**Funding:** This review article is not funded by any person or organization (not funded).

#### **Author details**

Mezgebu Legesse Habte1 \* and Etsegenet Assefa Beyene<sup>2</sup>

1 Department of Biochemistry, Harmaya University, School of Medicine and College of Health Sciences, Ethiopia

2 Department of Biochemistry, College of Health and Medical Sciences, Addis Ababa University, Addis Ababa, Ethiopia

\*Address all correspondence to: mezgebulegesse@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Biological Application and Disease of Oxidoreductase Enzymes DOI: http://dx.doi.org/10.5772/intechopen.93328*

#### **References**

**Ethical statement**

*Oxidoreductase*

funded).

**Author details**

**12**

Mezgebu Legesse Habte1

College of Health Sciences, Ethiopia

Ababa University, Addis Ababa, Ethiopia

provided the original work is properly cited.

the article are included in the article**.**

**Availability of data and material:** All necessary data and materials related to

**Funding:** This review article is not funded by any person or organization (not

\* and Etsegenet Assefa Beyene<sup>2</sup>

1 Department of Biochemistry, Harmaya University, School of Medicine and

2 Department of Biochemistry, College of Health and Medical Sciences, Addis

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: mezgebulegesse@gmail.com

[1] Trisolini L, Gambacorta N, Gorgoglion R, et al. FAD/NADH dependent oxidoreductases: From different amino acid sequences to similar protein shapes for playing an ancient function. Journal of Clinical Medicine. 2019;**8**:2117

[2] McDonald A. The Enzyme List Class 1—Oxidoreductases. Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB); 2019

[3] Gramss G, Rudeschko O. Activities of oxidoreductase enzymes in tissue extracts and sterile root exudates of three crop plants, and some properties of the peroxidase component. New Phytology. 1998;**138**:401-409

[4] Braune A, Gütschow M, Blau M. An NADH-dependent reductase from *Eubacterium ramulus* catalyzes the stereospecific heteroring cleavage of flavanones and flavanonols. Applied and Environmental Microbiology. 2019. DOI: 10.1128/AEM.01233-19

[5] Rendic S, Guengerich FP. Survey of human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chemical Research in Toxicology. 2015;**28**:38-42

[6] Martíneza AT, Ruiz-Dueñasa FJ, Camareroa S, et al. Oxidoreductases on their way to industrial biotransformations. Biotechnology Advances. 2017;**35**:815-831

[7] Chapman J, Ismail AE, Dinu CZ. Industrial applications of enzymes: Recent advances, techniques, and outlooks. Catalysts. 2018;**8**:238

[8] Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: Molecular mechanisms and pathophysiological implications. The Journal of Physiology. 2004;**555**(3): 589-606

[9] Chen C, Lü J-M, Yao Q. Hyperuricemia and XOR inhibitors. Medical Science Monitor. 2016;**22**: 2501-2512

[10] Raja MMM, Raja A, Imran MM, Santha AMI, Devasena K. Enzyme application in diagnostic application. Biotechnology. 2011;**10**(1):51-59

[11] Hoidal JR, Xu R, Huecksteadt T, Sanders KA, Pfeffer K, Sturrock AB. Lung injury and oxidoreductases. Environmental Health Perspectives. 1998;**106**(5):1235-1239

[12] Uravleva GF. Histochemical investigation of the activity of oxidoreductases in the skin lesions of lepromatous leprosy patients. Bulletin of the World Health Organization. 1972; **46**:813-819

[13] Pey AL, Megarity CF, Timson DJ. NAD(P)H quinone oxidoreductase (NQO1): An enzyme which needs just enough mobility, in just the right places. Bioscience Reports. 2019;**39**(1)

[14] Brass EP, Hiatt WR, Gardner AW, Hoppe CL. Decreased NADH dehydrogenase and ubiquinolcytochrome c oxidoreductase in peripheral arterial disease. American Journal of Physiology. Heart and Circulatory Physiology. 2001; **280**:H603-H609

[15] Fang Y, Gao N, Tian X, Zhou J, et al. Effect of P450 oxidoreductase polymorphisms on the metabolic activities of ten cytochrome P450s varied by polymorphic CYP genotypes in human liver microsomes. Cellular Physiology and Biochemistry. 2018;**47**: 1604-1616

[16] Flück CE, Tajima T, Pandey AV, et al. Mutant P450 oxidoreductase

causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nature Genetics. 2004;**36**(3)

[17] Younus H. Oxidoreductase: An overview and practical application. In: Biocatalysis. 2019. pp. 39-55

[18] Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology & Therapeutics. 2013; **138**:103-141

[19] Ramsay RR. Electron carriers and energy conservation in mitochondrial respiration. ChemTexts. 2019;**5**:9

[20] Porpaczy Z, Sumegi SB, Alkonyi I. Interaction between NAD-dependent isocitrate dehydrogenase, aketoglutarate dehydrogenase complex, and NADH:Ubiquinone oxidoreductase. Journal of Biochemistry. 1987;**262**(20): 950-9514

[21] Shestov AA, Liu X, Ser Z, et al. Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step. Biochemistry Human Biology and Medicine. 2014;**3**:e03342

[22] Mailloux RJ. Still at the center of it all; novel functions of the oxidative Krebs cycle. Bioenergetics. 2015;**4**:122. DOI: 10.4172/21677662.1000122

[23] Ponizovskiy MR. Role of Krebs cycle in the mechanism of stability internal medium and internal energy in an organism in norm and in mechanisms of cancer pathology. Modern Chemistry and Applications. 2016;**4**:191. DOI: 10.4172/2329-6798.1000191

[24] Kotb MI. Biological Oxidation (Electron transport chain— Chemiosmosis Oxidative Phosphorylation—Uncouplers). Presentation. Bio II-Spring; 2017

[25] Matsubayashi M, Inaoka DK, Komatsuya K, et al. Novel characteristics of mitochondrial electron transport chain from *Eimeria tenella*. Genes. 2019;**10**:29

Alcoholism. Berlin Heidelberg:

*DOI: http://dx.doi.org/10.5772/intechopen.93328*

*Biological Application and Disease of Oxidoreductase Enzymes*

boceprevir: A novel, first-generation inhibitor of the hepatitis C virus NS3/4A serine protease. Journal of Clinical and Translational Hepatology. 2013;**1**:22-32

[44] Daiju D, Takumi O, Yosifumi M, et al. Formate oxidase, an enzyme of the

oxidoreductase family, has a His-Arg pair and 8-formyl-FAD at the catalytic site. Bioscience, Biotechnology, and Biochemistry. 2011;**75**(9):1662-1667

[45] Chánique AM, Parra LP. Protein engineering for nicotinamide coenzyme specificity in oxidoreductases: Attempts

[46] Pollegioni L, Schonbrunn E, Siehl D. Molecular basis of glyphosate resistance —Different approaches through protein engineering. The FEBS Journal. 2011;

[47] Kumar K, Gambhir G, Dass A, et al. Genetically modified crops: Current status and future prospects. Planta.

[48] Zdunek-Zastocka E, Lips HS. Is xanthine dehydrogenase involved in response of pea plants (*Pisum sativum* L.) to salinity or ammonium treatment? Acta Physiologiae Plantarum. 2003;**25**:

[49] Hofmann NR. Opposing functions for plant xanthine dehydrogenase in response to powdery mildew infection: Production and scavenging of reactive oxygen species. The Plant Cell. 2016;

[50] Buchert J, Autio K. Using crosslinking enzymes to improve textural and other properties of food. Novel Enzyme Technology for Food

[51] Di Maio G, Pittia P, Mazzarino L, Maraschin M, Kuhnen S. Cow milk enriched with nanoencapsulated

glucose-methanol-choline

and challenges. Frontiers in Microbiology. 2018;**9**:194

**278**(16):2753-2766

2020;**251**:91

395-401

**28**(5):1001

Applications. 2007

[35] Yeung AK, Georgieva MG, Atanasov AG, Tzvetkovetics NT. Monoamine oxidases (MAOs) as privileged molecular targets in neuroscience. Research literature analysis. Frontiers in molecular neuroscience. 2019;**12**:143

Springer-Verlag; 1990

[36] Müller T, Möhr J-D.

Pharmacokinetics of monoamine oxidase B inhibitors in Parkinson's disease. Drug Metabolism & Toxicology. 2019;**15**(5):429-435

[37] Zhang Z, Hamada H, Gerk PM. Selectivity of dietary phenolics for inhibition of human monoamine oxidases A and B. BioMed Research

[38] Scott RR, Miller WL. Genetic and clinical features of P450 oxidoreductase deficiency. Hormonal Research. 2008;

[39] Abdelraheem EMM, Busch H, Hanefeld U, Tonin F. Biocatalysis explained: From pharmaceutical to bulk chemical production. Reaction Chemistry and Engineering. 2019;**4**:1878-1894

[40] Fernandes P. Enzymes in food processing: Condensed overview on strategies for better biocatalysts. Enzyme Research. 2010;**2010**(1):1-20

[41] Stefano AD, Marinelli L, Eusepi P, et al. Synthesis and biological evaluation of novel selenyl and sulfur-l-dopa derivatives as potential anti-Parkinson's disease agents. Biomolecules. 2019;**9**:239

[42] Bhalerao DS, Kumar A, Arkala R, et al. Synthesis and process optimization of boceprevir: A protease inhibitor drug.

[43] Howe AYM, Venkatraman S. The discovery and development of

Organic Process Research and Development. 2015;**19**(11):1559-1567

**15**

International. 2019;**23**:2019

**69**:266-275

[26] Ozougwu J. Physiology of liver. Research Gate. 2017;**4**:13-24

[27] Penner N, Woodward C, Prakash C. Drug metabolizing enzymes and biotransformation reactions. Oxidative Enzymes. 2012:546-565

[28] Schenkman JB. Historical Background and Description of the Cytochrome P450 Monooxygenase System. 1993

[29] Başaran R, Eke BC. Flavin containing monooxygenases and metabolism of xenobiotics. Turkish Journal of Pharmaceutical Sciences. 2017;**14**(1):90-94

[30] Basaran R, Benay CA. Flavin containing monooxygenases and metabolism of xenobioics. Turkish journal of pharmaceutical sciences. 2017;**14**(1):90

[31] Rossner R, Kaeberlein M, Leiser S. Flavin containing monooxygenases in aging and disease: Emerging roles for ancient enzymes. The Journal of Biological Chemistry. 2017;**292**(27): 11138-11146

[32] Haseba T, Ohno YA. New view of alcohol metabolism and alcoholism— Role of the high-Km Class III alcohol dehydrogenase (ADH3). International Journal of Environmental Research and Public Health. 2010;**7**(3):1076-1092

[33] Chang JS, Hsiao J-R, Chen C-H. ALDH2 polymorphism and alcoholrelated cancers in Asians: A public health perspective. Journal of Biomedical Science. 2017;**24**:19

[34] Agarwal DP et al. Alcohol Metabolism, Alcohol Intolerance, and *Biological Application and Disease of Oxidoreductase Enzymes DOI: http://dx.doi.org/10.5772/intechopen.93328*

Alcoholism. Berlin Heidelberg: Springer-Verlag; 1990

causes disordered steroidogenesis with and without Antley-Bixler syndrome.

[25] Matsubayashi M, Inaoka DK, Komatsuya K, et al. Novel

Genes. 2019;**10**:29

characteristics of mitochondrial electron transport chain from *Eimeria tenella*.

[26] Ozougwu J. Physiology of liver.

Drug metabolizing enzymes and biotransformation reactions. Oxidative

[27] Penner N, Woodward C, Prakash C.

Research Gate. 2017;**4**:13-24

Enzymes. 2012:546-565

System. 1993

2017;**14**(1):90-94

11138-11146

[28] Schenkman JB. Historical Background and Description of the Cytochrome P450 Monooxygenase

[29] Başaran R, Eke BC. Flavin containing monooxygenases and metabolism of xenobiotics. Turkish Journal of Pharmaceutical Sciences.

[30] Basaran R, Benay CA. Flavin containing monooxygenases and

metabolism of xenobioics. Turkish journal of pharmaceutical sciences. 2017;**14**(1):90

[31] Rossner R, Kaeberlein M, Leiser S. Flavin containing monooxygenases in aging and disease: Emerging roles for ancient enzymes. The Journal of Biological Chemistry. 2017;**292**(27):

[32] Haseba T, Ohno YA. New view of alcohol metabolism and alcoholism— Role of the high-Km Class III alcohol dehydrogenase (ADH3). International Journal of Environmental Research and Public Health. 2010;**7**(3):1076-1092

[33] Chang JS, Hsiao J-R, Chen C-H. ALDH2 polymorphism and alcoholrelated cancers in Asians: A public health perspective. Journal of Biomedical Science. 2017;**24**:19

[34] Agarwal DP et al. Alcohol

Metabolism, Alcohol Intolerance, and

Nature Genetics. 2004;**36**(3)

Biocatalysis. 2019. pp. 39-55

[18] Zanger UM, Schwab M.

**138**:103-141

*Oxidoreductase*

950-9514

**14**

[17] Younus H. Oxidoreductase: An overview and practical application. In:

Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation.

Pharmacology & Therapeutics. 2013;

[19] Ramsay RR. Electron carriers and energy conservation in mitochondrial respiration. ChemTexts. 2019;**5**:9

[20] Porpaczy Z, Sumegi SB, Alkonyi I. Interaction between NAD-dependent

ketoglutarate dehydrogenase complex, and NADH:Ubiquinone oxidoreductase. Journal of Biochemistry. 1987;**262**(20):

[21] Shestov AA, Liu X, Ser Z, et al. Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step. Biochemistry Human Biology and

[22] Mailloux RJ. Still at the center of it all; novel functions of the oxidative Krebs cycle. Bioenergetics. 2015;**4**:122. DOI: 10.4172/21677662.1000122

[23] Ponizovskiy MR. Role of Krebs cycle in the mechanism of stability internal medium and internal energy in an organism in norm and in mechanisms of cancer pathology. Modern Chemistry and Applications. 2016;**4**:191. DOI: 10.4172/2329-6798.1000191

[24] Kotb MI. Biological Oxidation (Electron transport chain— Chemiosmosis Oxidative Phosphorylation—Uncouplers). Presentation. Bio II-Spring; 2017

isocitrate dehydrogenase, a-

Medicine. 2014;**3**:e03342

[35] Yeung AK, Georgieva MG, Atanasov AG, Tzvetkovetics NT. Monoamine oxidases (MAOs) as privileged molecular targets in neuroscience. Research literature analysis. Frontiers in molecular neuroscience. 2019;**12**:143

[36] Müller T, Möhr J-D. Pharmacokinetics of monoamine oxidase B inhibitors in Parkinson's disease. Drug Metabolism & Toxicology. 2019;**15**(5):429-435

[37] Zhang Z, Hamada H, Gerk PM. Selectivity of dietary phenolics for inhibition of human monoamine oxidases A and B. BioMed Research International. 2019;**23**:2019

[38] Scott RR, Miller WL. Genetic and clinical features of P450 oxidoreductase deficiency. Hormonal Research. 2008; **69**:266-275

[39] Abdelraheem EMM, Busch H, Hanefeld U, Tonin F. Biocatalysis explained: From pharmaceutical to bulk chemical production. Reaction Chemistry and Engineering. 2019;**4**:1878-1894

[40] Fernandes P. Enzymes in food processing: Condensed overview on strategies for better biocatalysts. Enzyme Research. 2010;**2010**(1):1-20

[41] Stefano AD, Marinelli L, Eusepi P, et al. Synthesis and biological evaluation of novel selenyl and sulfur-l-dopa derivatives as potential anti-Parkinson's disease agents. Biomolecules. 2019;**9**:239

[42] Bhalerao DS, Kumar A, Arkala R, et al. Synthesis and process optimization of boceprevir: A protease inhibitor drug. Organic Process Research and Development. 2015;**19**(11):1559-1567

[43] Howe AYM, Venkatraman S. The discovery and development of

boceprevir: A novel, first-generation inhibitor of the hepatitis C virus NS3/4A serine protease. Journal of Clinical and Translational Hepatology. 2013;**1**:22-32

[44] Daiju D, Takumi O, Yosifumi M, et al. Formate oxidase, an enzyme of the glucose-methanol-choline oxidoreductase family, has a His-Arg pair and 8-formyl-FAD at the catalytic site. Bioscience, Biotechnology, and Biochemistry. 2011;**75**(9):1662-1667

[45] Chánique AM, Parra LP. Protein engineering for nicotinamide coenzyme specificity in oxidoreductases: Attempts and challenges. Frontiers in Microbiology. 2018;**9**:194

[46] Pollegioni L, Schonbrunn E, Siehl D. Molecular basis of glyphosate resistance —Different approaches through protein engineering. The FEBS Journal. 2011; **278**(16):2753-2766

[47] Kumar K, Gambhir G, Dass A, et al. Genetically modified crops: Current status and future prospects. Planta. 2020;**251**:91

[48] Zdunek-Zastocka E, Lips HS. Is xanthine dehydrogenase involved in response of pea plants (*Pisum sativum* L.) to salinity or ammonium treatment? Acta Physiologiae Plantarum. 2003;**25**: 395-401

[49] Hofmann NR. Opposing functions for plant xanthine dehydrogenase in response to powdery mildew infection: Production and scavenging of reactive oxygen species. The Plant Cell. 2016; **28**(5):1001

[50] Buchert J, Autio K. Using crosslinking enzymes to improve textural and other properties of food. Novel Enzyme Technology for Food Applications. 2007

[51] Di Maio G, Pittia P, Mazzarino L, Maraschin M, Kuhnen S. Cow milk enriched with nanoencapsulated

phenolic extract of jaboticaba (plinia peruviana). Journal of Food Science and technology. 2019;**56**(3):1165-1173

[52] Pandey VP, Awasthi M, Singh S, Tiwari S, Dwivedi UN. Comprehensive review on function and application of plant peroxidases. Journal of Biochemistry & Analytical Biochemistry. 2017;**6**:308

[53] Garrone A, Archipowa N, Zipfel PF, Hermann G, Dietzek B. Plant Protochlorophyllide Oxidoreductases A and B – Catalytic Efficiency and Initial Reaction Steps. Journal of biological chemistry. 2015;**290**(47):28530-28539

[54] Ho T, Chang C, Wu J, Huang I, et al. Recombinant expression of aldehyde dehydrogenase 2 (ALDH2) in *Escherichia coli* nissle 1917 for oral delivery in ALDH2-deficient individuals. bioRxiv. 2019. preprint

[55] Shi Y, van Rhijn JR, Bormann M, Mossink B, et al. Brunner syndrome associated MAOA dysfunction in human induced dopaminergic neurons results in dysregulated NMDAR expression and increased network activity. bioRxiv. 2019. preprint

[56] Nsiah-Sefaa A, McKenzie M. Combined defects in oxidative phosphorylation and fatty acid βoxidation in mitochondrial disease. Bioscience Reports. 2016;**36** art: e00313

[57] Chen X, Qi F, Dash RK, Beard DA. Kinetics and regulation of mammalian NADH-ubiquinone oxidoreductase (Complex I). Biophysical Journal. 2010; **99**:1426-1436

[58] Scheffler IE. Mitochondrial disease associated with complex I (NADH-CoQ oxidoreductase) deficiency. Journal of Inherited Metabolic Disease. 2015;**38**(3): 405-415

[59] Gupta N, Rutledge C. Pyruvate dehydrogenase complex deficiency: An unusual cause of recurrent lactic acidosis in a paediatric critical care unit. Journal of Critical Care Medicine. 2019; **5**(2):71-75

[60] Dean B, Chrisp GL, Quartararo M, et al. P450 oxidoreductase deficiency: A systematic review and meta-analysis of genotypes, phenotypes, and their relationships. The Journal of Clinical Endocrinology and Metabolism. 2020; **105**(3):e42-e52

[61] Cheng JB et al. Molecular genetics of 3beta-hydroxy-delta5-C27-steroid oxidoreductase deficiency in 16 patients with loss of bile acid synthesis and liver disease. The Journal of Clinical Endocrinology and Metabolism. 2003; **88**(4):1833-1841

[62] Lacher S, Bruttger J, Kalt B, et al. HMG-CoA reductase promotes protein prenylation and therefore is indispensible for T-cell survival. Cell Death & Disease. 2017;**8**:e2824

[63] Göbel A, Breining D, Rauner M, Hofbauer LC, Rachner TD. Induction of 3-hydroxy-3-methylglutaryl-CoA reductase mediates statin resistance in breast cancer cells. Cell Death & Disease. 2019;**10**(2):91

**17**

and oxyfunctionalized organic substrates.

**Chapter 2**

**Abstract**

biocatalytic

**1. Introduction**

*Sandhya Rani Gogoi*

Applications of Oxidoreductases

Oxidoreductases comprise of a large group of enzymes catalyzing the transfer of electrons from an electron donor to an electron acceptor molecule, commonly taking nicotinamide adenine dinucleotide phosphate (NADP) or nicotinamide adenine dinucleotide (NAD) as cofactors. Research on the potential applications of oxidoreductases on the growth of oxidoreductase-based diagnostic tests and better biosensors, in the design of inventive systems for crucial coenzymes regeneration, and in the creation of oxidoreductase-based approaches for synthesis of polymers and oxyfunctionalized organic substrates have made great progress. This chapter focuses on biocatalytic applications of oxidoreductases, since many chemical and biochemical transformations involve oxidation/reduction processes, developing practical applications of oxidoreductases has long been a significant target in biotechnology. Oxidoreductases are appropriate catalysts owing to their biodegradability, specificity and efficiency and may be employed as improved biocatalysts to substitute the toxic/expensive chemicals, save on energy/resources consumption, generate novel functionalities, or reduce complicated impacts on environment.

**Keywords:** oxidoreductases, cofactors, biosensors, coenzymes regeneration,

The various chemical transformations catalyzed by enzymes make these catalysts a key goal for utilization by the promising biotechnology industries. In the recent years, intense research in the field of enzyme technology has provided numerous approaches that facilitate the practical application of enzymes. This chapter emphasizes the application of oxidoreductases which catalyze the exchange of electrons amid the donor and acceptor molecules, in reactions involving electron transfer, proton/hydrogen extraction, hydride transfer, oxygen insertion, or other imperative steps. Oxidoreductases acquire advantage from the inclusion of different cofactors - for instance heme, flavin and metal ions - to catalyze redox reactions [1]. Majority of oxidoreductases are nicotinamide cofactor-dependent enzymes which have a high preference for nicotinamide adenine dinucleotide phosphate (NADP) or nicotinamide adenine dinucleotide (NAD) and they are further classified in six major classes which are oxidases, dehydrogenases, hydroxylases, oxygenases, peroxidases and reductases [2]. This chapter demonstrates the potential applications of oxidoreductases on the growth of oxidoreductase-based diagnostic tests and better biosensors, in the design of inventive systems for crucial coenzymes regeneration, and in the formation of oxidoreductase-based approaches for synthesis of polymers
