The Evolution of two cellular Shuttle Systems.

Peter Gauthier Since chemical reactions tend to equilibrium, it seems reasonable to assume that the driving evolutionary force of catabolic metabolism may have been the Free Energy Change of chemical reactions, as they proceed to equilibrium. The useful energy is preserved as bond energy and the rest is lost as heat. For this reason there seems to be a selective advantage for cells to use catabolic pathways that yield the most energy. If this is true then those catabolic reactions which yield the most energy would tend to prevail, and in this way the most energy available from molecules would be harnessed for cell use. During aerobic glycolysis, the coenzyme NAD+ is regenerated from its reduced form, NADH, by shuttle systems that move from the cytoplasm into the mitochondria. Since NAD+ is present in catalytic amounts, and does not enter the mitochondria to be oxidized, a shuttle system between the cytoplasm and the mitochondria is essential. Two examples of molecular systems that shuttle between the cytoplasm and the mitochondria are DHAP/AGP and OAA/MA systems (1). Of the two systems, more energy is derived from the OA/MA system (3 ATP molecules ) than from the DHAP/AGP system (2 ATP molecules). This disparity is due to the different intermediates of the electron transport chain that each reduces (2). Now if selection of one of these shuttle systems were based solely on the available energy that can be derived, then one could assume that the OAA/MA system would be selected exclusively. But in fact, some tissues utilize the DHAP/AGP system as a shuttle in spite of the fact that less energy is realized from this pathway. The cell can realize 38 ATP molecules from the complete oxidation of a glucose molecule using the OAA/MA system, whereas only 36 molecules of ATP are produced using the DHAP/AGP system. If these systems were being selected strictly on the basis of the available energy, then the OAA/MA system would always be the system of choice. But in some tissue the DHAP/AGP system is used so there must be some other selective advantage for the cell to use this system other than the energy that can be obtained. Perhaps the availability of the shuttle intermediates plays a determining role in the matter.

In this light, an explanation for the use of the DHAP/AGP system is the proximity of DHAP to the key reaction of glycolysis in which NADH is the product, namely the oxidation of PGAL to 3-PGA. Since DHAP is in equilibrium with PGAL, as PGAL is pulled off the equilibrium and oxidized to 3-PGA, there is a DHAP molecule available to act as a shuttle for each NADH that is produced in this reaction. So in this case availability may be more important to the selective process than the energetic imperative. The overriding determinant in this case may simply be whatever the traffic will bear and this may guide the selective process resulting in a system that delivers less energy simply because an easier route was available. It seems reasonable to assume that in the evolution of catabolic pathways, those reactions in which the most available energy could be harnessed for cell use would be selected. But since that isnt true in the DHAP/AGP case, and of the two shuttle systems which perform the same function the one resulting in less energy is used in some tissue, it would seem another principle is being tested here. It seems that natures repertoire is only as large as it has to be to meet the demands, and it doesnt necessarily result in a system that extracts the most chemical energy; the lesser of the two systems, energetically, has also survived. There is no need to go beyond this, so nature doesnt strive for perfection, i.e. to select the system from which the most energy is derived. The process of natural selection doesnt necessarily result in the best system energetically, but in regard the DHAP/AGP system, simply the more convenient.
1.

Shuttle reactions in the cytoplasm. NADH ------> AGP NADH ------> MA + + NAD+ NAD+

(a) DHAP + (b) OA +

2. Shuttle reactions in the mitochondria showing ATP yield. (a) AGP (b) MA + + FAD -----> DHAP + FADH2 + 2 ATP + NADH + 3 ATP

NAD+ ----->OA

Note: (a). The OA/MA system involves other intermediates (Glu & Asp), but the net effect is that MA diffuses into the mitochondria and OA is regenerated in the cytoplasm via the amino acids, Glu and Asp. (b). The ATP molecules generated may be less for each system but the relative ratio of the systems, OA/MA / DHAP/AGP is about the same so the principles still stand.

Glossary:
DHAP: AGP: OAA: MA: PGAL: 3-PGA Dihydroxyacetone phosphate Alpha glycerophosphate Oxaloacetic acid Malic acid Phosphoglyceraldehyde 3-Phosphoglycerate

References:
Origins. Speculations about the Spontaneous Generation of the first Biotic Structure, Peter Gauthier. BIOS Vol. 65 No. 4 (1995) Lehninger: Principles of Biochemistry. Worth Publishing 1982 Garrett & Grisham: Biochemistry. 2nd Ed. Saunders Publishing 1999

Peter Gauthier 1992