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Only the L-isomer is produced naturally, while racemic mixtures are produced synthetically and used commercially as food additives and energy supplements.

So what happens when we consume D-malate? Does it just partake in the Krebs cycle, the citrate-malate/malate-aspartate shuttles, and such like the L-isomer?

Or, does it just bioaccumulate and/or inhibit these processes? Until it gets excreted out?

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I do not have specific proof, but I strongly suspect that the answer to this question is NO on the basis of the following arguments.

  • The overwhelming majority of sugars, amino acids, carboxylic acids and other metabolites with and asymmetric carbon atom have been long known to occur in only a single enantiomeric form within living organisms. This was established long before the nature of the enzymes that catalyse their reactions were characterized.
  • Since the 1950s and 1960s we have understood that the stereo-specificity of enzymic reactions reflects the weak but binding of (co-)substrates to specific chemical groups of amino acid residues in the active site, and the subsequent flow of electrons between the bound components (often including the amino acid residues). The overall three-dimensional structure of the interactions that allow such catalysis only occur with one form of the enantiomeric metabolite.
  • The fact that malate (e.g. in fruit such as apples) only occurs in the L-form indicates that the reactions which involve it (predominantly malate dehydrogenase and fumarase) conform to the principle just expounded.
  • Although racemases (enzymes that interconvert enantiomers) exist for certain compounds in certain species, malate racemases have only been reported in obscure bacteria. They are not known to be present in man.

The problem is that this is so well established that studies with D-malate of relevance to the question are hard to find. One thing to do would be to examine the three-dimensional structure of malate dehydrogenase with a suitable malate analogue bound and model the enantiomer. This requires some work — a cursory trawl shows that usually the enzyme is crystalized with the product, oxaloacetate bound.

I have not looked at the mitochondrial transport system involved in the shuttle: something else for the poster to try. Nor can I find information on whether D-malate is taken up by the gut, and what its fate is if it is.

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  • $\begingroup$ Interesting! Just found ncbi.nlm.nih.gov/pmc/articles/PMC1185386 (back from 1970, found to inhibit gluconeogenesis from malate but without any effect on the TCA cycle otherwise) $\endgroup$
    – ManRow
    Oct 31, 2023 at 21:35
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    $\begingroup$ @ManRow — The problem with this type of paper is that it's all "what" and little "how". That's not to criticise the work, which in the context of the time provided data to test hypotheses about the pathways. However if people sell malate as a supplement you would think someone should do experiments following the fate of radiolabelled D-malate in, say, rats. Not the cutting edge of science, but you would think the FDA would demand something of the sort. $\endgroup$
    – David
    Nov 1, 2023 at 13:15
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    $\begingroup$ @ManRow — In case I did not make myself clear, the interest here was not in D-malate per se, but in what inhibitors might reveal about L-malate metabolism. $\endgroup$
    – David
    Nov 1, 2023 at 19:57
  • $\begingroup$ The existence of D-amino-acid oxidase (discovered by Krebs) is surely an exception to this argument $\endgroup$
    – user338907
    Nov 4, 2023 at 13:00
  • $\begingroup$ @user338907 — You need to explain more clearly which of my points it negates, and it would be of interest if you could mention what is known of the function of that enzyme. At the moment I don’t see any connection with D-malate. $\endgroup$
    – David
    Nov 4, 2023 at 13:59

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