Limits...
Uncertainty of prebiotic scenarios: the case of the non-enzymatic reverse tricarboxylic acid cycle.

Zubarev DY, Rappoport D, Aspuru-Guzik A - Sci Rep (2015)

Bottom Line: We consider the hypothesis of the primordial nature of the non-enzymatic reverse tricarboxylic acid (rTCA) cycle and describe a modeling approach to quantify the uncertainty of this hypothesis due to the combinatorial aspect of the constituent chemical transformations.Our results suggest that a) rTCA cycle belongs to a degenerate optimum of auto-catalytic cycles, and b) the set of targets for investigations of the origin of the common metabolic core should be significantly extended.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.

ABSTRACT
We consider the hypothesis of the primordial nature of the non-enzymatic reverse tricarboxylic acid (rTCA) cycle and describe a modeling approach to quantify the uncertainty of this hypothesis due to the combinatorial aspect of the constituent chemical transformations. Our results suggest that a) rTCA cycle belongs to a degenerate optimum of auto-catalytic cycles, and b) the set of targets for investigations of the origin of the common metabolic core should be significantly extended.

Show MeSH

Related in: MedlinePlus

Examples of auto-catalytic cycles found in the rTCA supernetwork.Panel A: cycles with the fewest modifications in the molecular sequence with respect to the rTCA cycle. Reordering of the reductive carboxylation and carboxylation steps “1” and “2” in two fragments of rTCA cycle (black boxes) yields three auto-catalytic cycles that have the closest molecular sequences to the rTCA. Panel B: a cycle with the fewest modifications in the reaction types sequence with respect to the rTCA cycle. The sequence of reaction types in rTCA cycle is “1 2 3 5 4 1 2 3 5 6 7” starting from the reductive carboxylation of acetate (See Fig. 1). Omission of the first carboxylation step “2” involving pyruvate leads to the cycle with the sequence “1 _ 3 5 4 1 2 3 5 6 7” with a very different molecular composition. Panel C: two cycles involving the molecules with the highest closeness centrality in rTCA network. Both sequences are based on glyoxylate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4306138&req=5

f5: Examples of auto-catalytic cycles found in the rTCA supernetwork.Panel A: cycles with the fewest modifications in the molecular sequence with respect to the rTCA cycle. Reordering of the reductive carboxylation and carboxylation steps “1” and “2” in two fragments of rTCA cycle (black boxes) yields three auto-catalytic cycles that have the closest molecular sequences to the rTCA. Panel B: a cycle with the fewest modifications in the reaction types sequence with respect to the rTCA cycle. The sequence of reaction types in rTCA cycle is “1 2 3 5 4 1 2 3 5 6 7” starting from the reductive carboxylation of acetate (See Fig. 1). Omission of the first carboxylation step “2” involving pyruvate leads to the cycle with the sequence “1 _ 3 5 4 1 2 3 5 6 7” with a very different molecular composition. Panel C: two cycles involving the molecules with the highest closeness centrality in rTCA network. Both sequences are based on glyoxylate.

Mentions: The similar picture emerges from the analysis of the redox properties of the molecules in the supernetwork. Previously-proposed conclusions about the predisposed nature of rTCA cycle3 in part relied on the analysis of intensive characteristics of the rTCA cycle molecules such as thermodynamic stability per carbon atom and degree of reduction per carbon atom. Following Ref. 3, we define the reducing potential per carbon atom taken from the environment to form molecule A as the ratio y/x determined from a formal reaction xCO2 + yH2 → A + zH2O. As a counterpart of Figure 2 in Ref. 3, Figure 4A shows theoretical estimates of the free energy of formation computed in aqueous solution (see Methods) per carbon atom plotted against reducing potential for all molecules of the generated supernetwork. Molecules of rTCA cycle belong to the central part of a broad distribution and have neighbors with comparable or more favorable combinations of stability and reducing potential. For example, the cycles obtained by permutations of reductive carboxylation and carboxylation steps (Fig. 5A) would qualify as more favorable on thermodynamic grounds. They proceed via malonate which is more stable than pyruvate with −176 vs. −114 kcal/mol per 3 carbon atoms, and/or 1, 1, 2-ethanetricarboxylate that is more stable than 2-ketoglutarate with −254 vs. −199 kcal/mol per 5 carbon atoms.


Uncertainty of prebiotic scenarios: the case of the non-enzymatic reverse tricarboxylic acid cycle.

Zubarev DY, Rappoport D, Aspuru-Guzik A - Sci Rep (2015)

Examples of auto-catalytic cycles found in the rTCA supernetwork.Panel A: cycles with the fewest modifications in the molecular sequence with respect to the rTCA cycle. Reordering of the reductive carboxylation and carboxylation steps “1” and “2” in two fragments of rTCA cycle (black boxes) yields three auto-catalytic cycles that have the closest molecular sequences to the rTCA. Panel B: a cycle with the fewest modifications in the reaction types sequence with respect to the rTCA cycle. The sequence of reaction types in rTCA cycle is “1 2 3 5 4 1 2 3 5 6 7” starting from the reductive carboxylation of acetate (See Fig. 1). Omission of the first carboxylation step “2” involving pyruvate leads to the cycle with the sequence “1 _ 3 5 4 1 2 3 5 6 7” with a very different molecular composition. Panel C: two cycles involving the molecules with the highest closeness centrality in rTCA network. Both sequences are based on glyoxylate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4306138&req=5

f5: Examples of auto-catalytic cycles found in the rTCA supernetwork.Panel A: cycles with the fewest modifications in the molecular sequence with respect to the rTCA cycle. Reordering of the reductive carboxylation and carboxylation steps “1” and “2” in two fragments of rTCA cycle (black boxes) yields three auto-catalytic cycles that have the closest molecular sequences to the rTCA. Panel B: a cycle with the fewest modifications in the reaction types sequence with respect to the rTCA cycle. The sequence of reaction types in rTCA cycle is “1 2 3 5 4 1 2 3 5 6 7” starting from the reductive carboxylation of acetate (See Fig. 1). Omission of the first carboxylation step “2” involving pyruvate leads to the cycle with the sequence “1 _ 3 5 4 1 2 3 5 6 7” with a very different molecular composition. Panel C: two cycles involving the molecules with the highest closeness centrality in rTCA network. Both sequences are based on glyoxylate.
Mentions: The similar picture emerges from the analysis of the redox properties of the molecules in the supernetwork. Previously-proposed conclusions about the predisposed nature of rTCA cycle3 in part relied on the analysis of intensive characteristics of the rTCA cycle molecules such as thermodynamic stability per carbon atom and degree of reduction per carbon atom. Following Ref. 3, we define the reducing potential per carbon atom taken from the environment to form molecule A as the ratio y/x determined from a formal reaction xCO2 + yH2 → A + zH2O. As a counterpart of Figure 2 in Ref. 3, Figure 4A shows theoretical estimates of the free energy of formation computed in aqueous solution (see Methods) per carbon atom plotted against reducing potential for all molecules of the generated supernetwork. Molecules of rTCA cycle belong to the central part of a broad distribution and have neighbors with comparable or more favorable combinations of stability and reducing potential. For example, the cycles obtained by permutations of reductive carboxylation and carboxylation steps (Fig. 5A) would qualify as more favorable on thermodynamic grounds. They proceed via malonate which is more stable than pyruvate with −176 vs. −114 kcal/mol per 3 carbon atoms, and/or 1, 1, 2-ethanetricarboxylate that is more stable than 2-ketoglutarate with −254 vs. −199 kcal/mol per 5 carbon atoms.

Bottom Line: We consider the hypothesis of the primordial nature of the non-enzymatic reverse tricarboxylic acid (rTCA) cycle and describe a modeling approach to quantify the uncertainty of this hypothesis due to the combinatorial aspect of the constituent chemical transformations.Our results suggest that a) rTCA cycle belongs to a degenerate optimum of auto-catalytic cycles, and b) the set of targets for investigations of the origin of the common metabolic core should be significantly extended.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.

ABSTRACT
We consider the hypothesis of the primordial nature of the non-enzymatic reverse tricarboxylic acid (rTCA) cycle and describe a modeling approach to quantify the uncertainty of this hypothesis due to the combinatorial aspect of the constituent chemical transformations. Our results suggest that a) rTCA cycle belongs to a degenerate optimum of auto-catalytic cycles, and b) the set of targets for investigations of the origin of the common metabolic core should be significantly extended.

Show MeSH
Related in: MedlinePlus