Abstract
The evolutionary origin of the Krebs citric acid cycle has been for a long time a model case in the understanding of the origin and evolution of metabolic pathways: How can the emergence of such a complex pathway be explained? A number of speculative studies have been carried out that have reached the conclusion that the Krebs cycle evolved from pathways for amino acid biosynthesis, but many important questions remain open: Why and how did the full pathway emerge from there? Are other alternative routes for the same purpose possible? Are they better or worse? Have they had any opportunity to be developed in cellular metabolism evolution? We have analyzed the Krebs cycle as a problem of chemical design to oxidize acetate yielding reduction equivalents to the respiratory chain to make ATP. Our analysis demonstrates that although there are several different chemical solutions to this problem, the design of this metabolic pathway as it occurs in living cells is the best chemical solution: It has the least possible number of steps and it also has the greatest ATP yielding. Study of the evolutionary possibilities of each one-taking the available material to build new pathways-demonstrates that the emergence of the Krebs cycle has been a typical case of opportunism in molecular evolution. Our analysis proves, therefore, that the role of opportunism in evolution has converted a problem of several possible chemical solutions into asingle-solution problem, with the actual Krebs cycle demonstrated to be the best possible chemical design. Our results also allow us to derive the rules under which metabolic pathways emerged during the origin of life.
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Abbreviations
- pyr:
-
pyruvate
- OAA:
-
oxaloacetate
References
Annet RG, Kosicki GW (1969) Oxalacetate keto-enol tautomerase. Purification and characterization. J Biol Chem 244:2059–2067
Baldwin JE, Krebs H (1981) The evolution of metabolic cycles. Nature 291:381–382
Beatty JT, Gest H (1981) Biosynthetic and bioenergetic functions of citric acid cycle reactions inRhodopseudomonas capsulata. J Bacteriol 148:584–593
Brenner S (1994) Afterword. Chem Biol Introd 28:xxviii
Buchanan BB, Arnon DI (1990) A reverse Krebs cycle in photosynthesis: consensus at last. Photosynth Res 24:47–53
Dawkins R (1986) The blind watchmaker. Longman Scientific, London
Dawkins R (1994) The eye in a twinkling. Nature 368:690–691
Evans MCW, Buchanan BB, Arnon DI (1966) A new ferredoxin dependent carbon reduction cycle in a photosynthetic bacterium. Proc Natl Acad Sci USA 55:928–934
Flint DH, Nudelman A, Calabrese JC, Gottlieb HE (1992) Enol oxalacetic acid exists in the Z form in the crystalline state and in solution. J Org Chem 57:7270–7274
Gest H (1981) Evolution of the citric acid cycle and respiratory energy conversion in prokaryotes. FEMS Microbiol Lett 12:209–215
Gest H (1987) Evolutionary roots of the citric acid cycle in prokaryotes. Biochem Soc Symp 54:3–16
Hochachka PW (1991) Design of energy metabolism. In: Prosser CL (ed) Comparative animal physiology, 4th ed, vol 1, Wiley-Liss, New York, pp 325–351
Hochachka PW, Mustafa T (1972) Invertebrate facultative anaerobiosis. Science 178:1056–1060
Jacob F (1977) Evolution and tinkering. Science 196:1161–1166
Kay J, Weitzman DJ (eds) (1987) Krebs' citric acid cycle—half a century and still turning. (Biochem Soc Symp vol 54). The Biochemical Society, London
Lawless JG, Zeitman B, Pereira WE, Summons RE, Duffield AM (1974) Dicarboxylic acids in the Murchison meteorite. Nature 251: 40–42
Mason SF (1992) Chemical evolution. Clarendon Press, Oxford, pp 122–128
Meléndez-Hevia E (1990) The game of the pentose phosphate cycle: a mathematical approach to study the optimization in design of metabolic pathways during evolution. Biomed Biochim Acta 49:903–916
Meléndez-Hevia E, Isidoro A (1985) The game of the pentose phosphate cycle. J Theor Biol 117:251–263
Meléndez-Hevia E, Torres NV (1988) Economy of design in metabolic pathways: further remarks on the pentose phosphate cycle. J Theor Biol 132:97–111
Meléndez-Hevia E, Waddell TG, Shelton ED (1993) Optimization of molecular design in the evolution of metabolism: the glycogen molecule. Biochem J 295:477–483
Meléndez-Hevia E, Waddell TG, Montero F (1994) Optimization of metabolism: the evolution of metabolic pathways toward simplicity through the game of the pentose phosphate cycle. J Theor Biol 166:201–220
Mortlock RP (ed) (1992) Evolution of metabolic function. CRC Press, Boca Raton, FL
Schauder R, Eikmanns B, Thauer RK, Widdel F, Fuchs G (1986) Acetate oxidation to CO2 in anaerobic bacteria via a novel pathway not involving reactions of the citric acid cycle. Arch Microbiol 145:162–172
Serratosa F (1990) Organic Chemistry in action. Elsevier, Amsterdam
Serratosa F, Xicart J (1990) Chaos (Computerisation and heuristic applied to organic synthesis). Computer program. Elsevier, Amsterdam
Sporman AM, Thauer RK (1988) Anaerobic acetate oxidation to CO2 byDesulfotomaculum acetoxidans. Demonstration of enzymes required for the operation of an oxidative acetyl-CoA/carbon monoxide dehydrogenase pathway. Arch Microbiol 150:374–380
Thauer RK (1988) Citric acid cycle, 50 years on. Modifications and an alternative pathway in bacteria. Eur J Biochem 176:497–508
Waddell TG, Geevarghese SK, Henderson BS, Pagni RM, Newton JS (1989) Chemical evolution of the citric acid cycle: sunlight and ultraviolet photolysis of cycle intermediates. Orig Life 19:603–607
Waddell TG, Henderson BS, Morris RT, Lewis CM, Zimmermann AG (1987) Chemical evolution of the citric acid cycle: sunlight photolysis of α-ketoglutaric acid. Orig Life 17:149–153
Waddell TG, Miller TJ (1992) Chemical evolution of the citric acid cycle: sunlight photolysis of the aminoacids glutamate and aspartate. Orig Life 21:219–223
Weitzman PDJ (1985) Evolution of the citric acid cycle. In: Schleifer KH, Stackebrandt E (eds) Evolution of prokaryotes, Academic Press, London, pp 253–273
Zeitman B, Chang S, Lawless JG (1974) Dicarboxylic acids from electric discharge. Nature 251:42–43
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Meléndez-Hevia, E., Waddell, T.G. & Cascante, M. The puzzle of the Krebs citric acid cycle: Assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution. J Mol Evol 43, 293–303 (1996). https://doi.org/10.1007/BF02338838
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DOI: https://doi.org/10.1007/BF02338838