How little we know

Well it’s basic biochem 101, but enzymes only allow equilibrium to be reached faster (by lowering activation energy), they never change it. This came as a shock to the authors of [ Proc. Natl. Acad. Sci. vol. 112 pp. 6601 – 6606 ’15 ] when Cytosolic Nonspecific DiPeptidase 2 (CNDP2), a proteolytic enzyme, was found to tack the carboxyl group of lactic acid onto the amino group of a variety of amino acids, essentially running the proteolytic reaction in reverse. Why? Because intracellular levels of lactic acid and amino acids are in the high microMolar to milliMolar range. It’s Le Chatelier’s principle in action.

The compounds are called N-Lactoyl amino acids. No one had ever seen them before. They are part of the ‘metabolome’ — small molecules found in our bodies. God knows what they do. The paper was really shocking to me for another reason, because I had no idea how many members the metabolome has.

How large is the metabolome? Make a guess.

Well METLIN (https://metlin.scripps.edu/index.php has 240,000, and Human Metabolome DataBase http://www.hmdb.ca/metabolites?c=hmdb_id&d=up&page=1676 has 42,000. I doubt that we know what they are all doing. Undoubtedly some of them are binding to proteins producing physiologic effects. Drug chemists may be mimicking some of them unknowingly, producing untoward and unexpected side effects.

What’s even more shocking to me is the following statement from the paper. State of the art untargeted metabolomics studies still report ‘up to’ 40% unidentified, but potentially important metabolitcs which can be detected reproducibly. The unknown metabolites are only rarely characterized because of the extensive work required for de novo structure determination..

So we really don’t know everything that’s out there in our bodies, and even if we did, we don’t know what they are doing. Drug discovery is hard because we only dimly understand the system we are trying to manipulate. Until I read this paper, I had no idea just how dim this is.

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