Encyclopedia
Protons (H+) are highly reactive, they are always solvated or disolvated. In presence of water acids dissociate in an exothermic reaction into the acid-anion and H+[H2O]n. Proton transport chain (PTC) hypothesis was developed for enzyme-complexes. The assumption that the enzyme-enzyme interaction is water-free entails that an acid synthesized from enzyme A is transferred as acid to enzyme B. The PTC-hypothesis was first discussed for the GAPDH-LDHm complex. GAPDH formed NADH-H+ is transferred to LDHm. The consequence of water-free transfer is that the concentration of NADH-H+ is infinite. An infinite concentration unidirectionally drives the LDHm catalysed reaction. LDHm activity strictly depends on delivery (mol/s) of NADH-H+. The PTC hypothesis replaces the well-established concept of (single) enzyme-kinetics by enzyme-complex kinetics. Quite well-known proteins complexes driven by PTC are: the pyruvatedehydrogenase complex (PDHc) or the citric acid cycle.
- PTC
Protons (H+) are vanished from didactic biochemistry. A century ago, O.F. Meyerhof set glycolysis as the degradation of glucose (C6H12O6) to two molecules lactic acid 2 (C3H6O3) [1]. Today, the stoichiometry to metabolize glucose to two lactic acid is generally unknown. In 1953, H.A. Krebs was honoured with the Noble Prize for the discovery of the citric acid cycle. Krebs presented lactic acid as substrate of a cycle unidirectionally cycling acids [2]. Today, the acid-anion pyruvate was considered as substrate of Krebs “citrate cycle”. The change from Krebs scientifically based model to an alchemistic citrate cycle started quite early. In 1949 Kennedy and Lehninger investigated mitochondrial function on isolated mitochondria [3]. Kennedy and Lehninger used and determined carboxylates such as, pyruvate, malate, a-ketoglutarate and citrate. They discussed their data on basis of Krebs citric acid cycle, but phrases such as: “.oxidation of pyruvate and other intermediates of the Krebs cycle.” and “…aerobic citrate formation from pyruvate when malate served as a source of oxaloacetate.” misquoted Krebs acid cycle. But, misquote is incorrect, because Kennedy and Lehninger missed to quote one manuscript of Krebs. Lehningers “citrate cycle” has conquered the world.
Kennedy and Lehninger also mentioned “Fluoride was added to inhibit enolase and the end-point measured manometrically indicated the formation of 3-phoshoglyceric acid, which causes CO2 liberation from bicarbonate”. In Lehningers textbooks 3-phoshoglyceric acid as product of phosphoglycerate kinase (PGK) catalysed reaction is simplified to 3-phosohoglycerate
The PTC hypothesis discussed plasma membrane located PGK in complex with proton-linked monocarboxylate transporter 4 (MCT4). Permanent delivery of 3-phoshoglyceric acid drives MCT4 to unidirectionally export monocarboxylic acids [4] [5] [6] [7].
Plasma membrane located MCT1 is discussed in complex with carbonic anhydrase II (CAII). Permanent export of carbonic acid (H2CO3) drives MCT1 to unidirectionally import monocarboxylic acids [4] [5] [6] [7].
Mitochondrial membrane located LDHh-MCT1 was discussed to catalyse the first reaction of Krebs citric acid cycle: oxidation of lactate to pyruvate and membrane transfer of pyruvic acid to the PDHc complex.
Mitochondrial membrane located LDHh-MCT1 was also introduced to pyruvic acid to pyruvate carboxylase as substrate of oxaloacetic acid synthesis [4] [5] [6] [7].
The proposed citric acid cycle 1.1 balances burning of lactic acid and malic acid synthesis. Citric acid cycle 1.1 provides the mechanism of the data O.F. Meyerhof presented at his Noble Prize lecture: up-taken lactic acid is burned as well used as building block [8]. Citric acid cycle 1.1 illustrates the molecular mechanism for: synthesis is the product of degradation and thereby the transfer of the 4th law of thermodynamics to biologic process [9]. Textbooks, such as A. Lehningers Biochemistry, propagate maximal entropy and thereby exclude ordered structures, such as membranes, enzyme-complexes, metabolons, organelles, cells, brief biologic systems, the PTC hypothesis .
- Meyerhof O. RECENT INVESTIGATIONS ON THE AEROBIC AND AN-AEROBIC METABOLISM OF CARBOHYDRATES. J Gen Physiol. 1927;8: 531–542. doi:10.1085/jgp.8.6.531
- The Nobel Prize in Physiology or Medicine 1953. In: NobelPrize.org [Internet]. [cited 11 Nov 2020]. Available: https://www.nobelprize.org/prizes/medicine/1953/krebs/lecture/
- Kennedy EP. and Lehninger AL. Oxidation of fatty acids and tricarboxylic acid intermediates by isolated rat mitochondria. JBC 1949 Available: https://www.jbc.org/content/179/2/957.full.pdf
- Roosterman D, Meyerhof W, Cottrell GS. Proton Transport Chains in Glucose Metabolism: Mind the Proton. Front Neurosci. 2018;12. doi:10.3389/fnins.2018.00404
- Roosterman D, Cottrell GS. The two-cell model of glucose metabolism: a hypothesis of schizophrenia. Mol Psychiatry. 2021. doi:10.1038/s41380-020-00980-4
- Roosterman D, Cottrell GS. Rethinking the Citric Acid Cycle: Connecting Pyruvate Carboxylase and Citrate Synthase to the Flow of Energy and Material. Int J Mol Sci. 2021;22. doi:10.3390/ijms22020604
- Roosterman D, Cottrell GS. Astrocytes and neurons communicate via a monocarboxylic acid shuttle. AIMS Neurosci. 2020;7: 94–106. doi:10.3934/Neuroscience.2020007
- The Nobel Prize in Physiology or Medicine 1922. In: NobelPrize.org [Internet]. [cited 25 Dec 2020]. Available: https://www.nobelprize.org/prizes/medicine/1922/summary/
- Glansdorff P, Prigogine I. Thermodynamic Theory of Structure, Stability and Fluctuations. London, New York: John Wiley & Sons Ltd; 1971.
This entry is adapted from the peer-reviewed paper 10.3390/ijms22020604
