**1. Rise of the quinones**

As life began to emerge in the seas of primordial Earth, one of the first orders of business was the construction of a plasma membrane to protect and concentrate biomolecules in the cytoplasm of what would become the first cell. This served to increase the efficiency of the biochemical reactions necessary for growth and propagation. The constant influx of salt water across the plasma membrane, however, would have led to extremely high internal osmotic pressure in what were essentially bags of chemicals, necessitating the invention of efflux pumps to drive

© 2017 The Author(s). Licensee InTech. 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. © 2017 The Author(s). Licensee InTech. 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.

ions back out into the surrounding milieu. These early efflux pumps most likely exported protons at the expense of ATP, which the cells were forced to make through substrate‐level phosphor‐ ylation, an inefficient process. However, leakage of protons back into the cell could drive the ATPase in the reverse direction, thus linking the extrusion of protons to the creation of cellular energy.

toxic gas–oxygen. Among the many harmful effects of an oxygenated atmosphere were the generation of reactive oxygen species, which poisoned the metabolic pathways of early microbial cells by destroying important cofactors and enzymes [3]. In this noxious environ‐ ment lay opportunity, however, as oxygen could serve as an extremely effective electron acceptor if cells could evolve mechanisms for reducing it as part of their electron transport chains. Once again quinones mediated a metabolic breakthrough, linking the reduction of oxygen to membrane components via cytochrome oxidases. This process of aerobic respiration led to an estimated 16‐fold increase in the capacity to generate ATP [4] and may have opened

From Protein Folding to Blood Coagulation: Menaquinone as a Metabolic Link between Bacteria and Mammals

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The metabolic flexibility of quinones means that their use is not limited simply to the respira‐ tory chains of microbes or the photosynthetic centers of plants. Many higher‐order organisms not only incorporated quinones into their respiratory chains, but have utilized these highly effective molecular wires in many different redox‐dependent reactions. While the quinones

The major quinones found in nature are ubiquinone (UQ), menaquinone (MK), and phyllo‐ quinone (K1) (**Figure 1**). They differ not only in structure but also in their redox potentials, so the incorporation of one or the other as a cofactor allows for fine‐tuning of electron transfer reactions. The distribution in nature of genes involved in menaquinone biosynthesis suggests that it was most likely the original quinone; this is supported by the observation that mena‐ quinone is readily oxidized in aerobic environments, suggesting that it existed long before the appearance of oxygen [6]. There are many different species of menaquinone, though they differ only in the length of their isoprenyl side chains. These differences are reflected in the nomen‐ clature of menaquinones, wherein the number of isoprene units is indicated (i.e., MK‐4). Phylloquinone, usually considered distinct from the menaquinones, is merely MK‐4 with a

the door to the development of complex eukaryotic life [5].

are ancient, they remain very important to life on this planet.

more heavily saturated lipophilic tail.

**Figure 1.** Structures of common quinones.

**2. Biosynthesis of menaquinone and phylloquinone**

Aside from the issue of osmotic pressure, the plasma membrane also created a conundrum in that the organic molecules necessary to drive metabolism were prevented entry. Thus, cells developed membrane‐associated transporters capable of importing such nutrients. Catabo‐ lism of these organic molecules provided the cells with necessary building blocks and resulted in the liberation of electrons, which could then be collected on redox‐active molecules like NAD+ or FAD+, reducing them to NADH and FADH2.

To regenerate the pools of electron carriers, these ancient microbes resorted to fermentation, the process by which electrons are dropped onto self‐derived organic molecules. This freed up NAD+ and FAD+ to participate in more rounds of catabolism of carbon sources, thus driving metabolism. However, fermentation is an inefficient process and thus limited the growth rate and abundance of these microbes. Only when the enzymes involved in fermentation (i.e., nitrate reductase, fumarate reductase) evolved to associate with the plasma membrane did these ancient microbes begin to tap into the power they needed to flourish. Now, the process of passing electrons onto terminal acceptors could be coupled to the extrusion of protons into the extracellular space. With greater numbers of protons pumped out of the cell, their leakage back across the membrane could greatly increase the amount of ATP generated [1]. In essence, the cells could target these molecular machines to the membrane to produce the chemical energy necessary to fuel metabolism. The effect could be further amplified by linking these redox reactions together, but that required cofactors capable of accepting and donating electrons to act as molecular wires. The earliest such cofactors were likely iron‐sulfur clusters and flavins, but these were not readily inserted into the highly lipophilic environment of the plasma membrane. Thus arose the quinones, which are fat‐soluble redox molecules capable of associating with membrane‐embedded enzymes. By linking together several modular redox complexes into an electron transport chain capable of extruding protons, quinones potentiated a huge leap forward in bioenergetics and greatly increased the capacity for complexity in biological systems.

To maximize the utility of having quinones available in their membranes, these ancient microbes needed to find a way to tap into more plentiful electron donors and acceptors. One potential source of electrons present in abundance on primordial Earth was water. However, the vast amounts of energy necessary to pull electrons from water presented a formidable obstacle to its utilization. Only when high‐energy solar radiation came to be employed in the process known as photosynthesis were "cyanobacteria" successful in linking the fixation of CO2 to hydrolysis [2]. Quinones were key to the evolution of photosystem I, yet another example of their power and adaptability in biological systems.

While the increased access to electrons represented a potential windfall to energy‐starved cells, the development of photosynthesis was nonetheless catastrophic to life on Earth. Concomitant with the liberation of electrons from water by photosynthesis was the production of a new and toxic gas–oxygen. Among the many harmful effects of an oxygenated atmosphere were the generation of reactive oxygen species, which poisoned the metabolic pathways of early microbial cells by destroying important cofactors and enzymes [3]. In this noxious environ‐ ment lay opportunity, however, as oxygen could serve as an extremely effective electron acceptor if cells could evolve mechanisms for reducing it as part of their electron transport chains. Once again quinones mediated a metabolic breakthrough, linking the reduction of oxygen to membrane components via cytochrome oxidases. This process of aerobic respiration led to an estimated 16‐fold increase in the capacity to generate ATP [4] and may have opened the door to the development of complex eukaryotic life [5].

The metabolic flexibility of quinones means that their use is not limited simply to the respira‐ tory chains of microbes or the photosynthetic centers of plants. Many higher‐order organisms not only incorporated quinones into their respiratory chains, but have utilized these highly effective molecular wires in many different redox‐dependent reactions. While the quinones are ancient, they remain very important to life on this planet.
