**1. Introduction**

Gene multiplicity or redundancy is a characteristic of microorganisms and means there are two or more genes coding for proteins that perform the same function. Inactivation of any of these genes does not affect or has little relevance to the biological phenotype [1]. Gene redundancy has been observed in all organisms, including prokaryotes and eukaryotes, and is particularly important for actinobacteria that produce metabolites of industrial interest [2]. The most significant property of *Streptomyces* species is the production of several secondary metabolites (antibiotics and biologically active compounds) that can be generated at the industrial level. These metabolites are beneficial and indispensable for human and

animal health [3]. Although the structures of secondary metabolites are diverse, they have been classified into at least five classes (sugar, polyketide, shikimate, amino acid, and terpene pathways) based on the precursor molecules incorporated during their biosynthesis. All precursors are derived from central primary metabolism, glycolysis (Embden–Meyerhof–Parnas EM pathway), the pentose phosphate pathway (PP), and the tricarboxylic acid (TCA) cycle. Glucose-6-phosphate, a precursor of aminoglycosides, is supplied from the early stage of the EM pathway, and acetyl-CoA and succinyl-CoA as precursors of polyketides are supplied from the final stage of the EM pathway and TCA cycle, respectively. Aromatic amino acids, as precursors of chloramphenicol, are supplied from the PP pathway, whereas other amino acids are supplied from the central metabolism to be precursors of peptide antibiotics. Acetyl-CoA, glyceraldehyde-3-phosphate, and pyruvate (PYR) are precursors of isopentenyl diphosphate and dimethylallyl diphosphate, which are the building blocks of terpenes. Malonyl-CoA, methylmalonyl-CoA, and ethylmalonyl-CoA are used as the extension units in macrolide antibiotic biosynthesis [4], and reduced cofactor (NADPH) is used during secondary metabolite biosynthesis and is generated from the PP pathway and TCA cycle. Accordingly, the dynamics of central metabolism, including the EM and PP pathways and the TCA cycle, which generate primary metabolites (as precursors for secondary metabolites) and cofactors, will influence the biosynthetic process of secondary metabolites [5].

One little-studied area is the carbon metabolism in these organisms. Few studies have examined the presence of genes that participate in the glycolytic pathway, TCA cycle, or phosphoenolpyruvate-pyruvate-oxaloacetate (PEP-PYR-OXA) node. In general, microorganisms metabolize glucose through the glycolysis and hexose monophosphate pathways [6]. Many of the intermediates in these metabolic pathways are used to synthesize other essential bacterial compounds (amino acids, polysaccharides, nucleic acids, lipids, fatty acids, and antibiotics).

The EMP pathway consists of nine reactions, in which the final product is pyruvate. The first reaction consists of the isomerization of glucose 6-phosphate to fructose 6-phosphate catalyzed by phosphoglucose isomerase. Another phosphate with adenosine triphosphate (ATP) as the donor is incorporated into fructose 6-phosphate by phosphofructokinase. The next step is the cleavage of fructose 1,6-diphosphate by aldolase, generating dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which can be interconverted by triose phosphate isomerase. Glyceraldehyde 3-phosphate is oxidized to 1,3-diphosphoglycerate by glyceraldehyde 3-phosphate dehydrogenase to generate NADH. The phosphoglycerate kinase-catalyzed reaction generates an ATP molecule, an example of substrate-level phosphorylation. The 3-phosphoglycerate is converted to 2-phosphoglycerate by phosphoglycerate mutase and is subsequently dehydrated by enolase. Phosphoenolpyruvate (PEP) is used to generate another molecule of ATP and PYR through a reaction catalyzed by pyruvate kinase. Then, four ATP molecules are generated, and two high-energy phosphate bonds are used; thus, the net gain is two ATPs per oxidized glucose molecule [6].

The TCA cycle is one of the most important metabolic pathways, not only as part of catabolism but also as an important intermediate for amino acid biosynthesis and synthesizing secondary metabolites. Generally, the citric acid cycle is the main oxidation pathway for carbon chains of carbohydrates, fatty acids, and many amino acids to CO2 and water. At each turn of the cycle, two molecules of CO2 are released. Most of the energy generated during oxidation is stored as NADH, FADH, or ATP (or GTP).

Because the intermediates of the TCA cycle are used as precursors in other pathways, they are replenished through anaplerotic reactions. Under normal conditions, the reactions that take intermediates in the cycle and those that replace them are kept in dynamic equilibrium; therefore, their concentrations remain

constant. The most common anaplerotic reactions are those in which PYR or PEP are converted to Oxaloacetic acid (OXA) or malate. For example, this first reaction can be mediated by PEP carboxylase in some plants, yeasts, and bacteria or by the malic enzyme (ME), which is widely distributed in prokaryotes and eukaryotes [7].
