Scientists Discover Previously Unknown Branch of Tryptophan Metabolism in Humans
Researchers have identified a previously unknown enzymatic reaction in the human kynurenine pathway, revealing that the protein ASPDH acts as a reductase to produce a novel amino acid called L-2-aminohex-3-enedioic acid. The kynurenine pathway is the primary route by which animals break down tryptophan, generating NAD and numerous bioactive compounds, but its downstream steps in eukaryotes had remained poorly characterized. This discovery expands the known catalog of endogenous amino acids and demonstrates how large-scale comparative genomics across thousands of species can uncover hidden reactions in human biochemistry.
A new study published on bioRxiv reports that the human enzyme ASPDH functions as an NAD(P)H-dependent 2-aminomuconate reductase, catalyzing a previously uncharacterized step in tryptophan catabolism via the kynurenine pathway. By analyzing evolutionary data from over 5,000 eukaryotic species, the researchers identified two distinct genes operating downstream of the unstable intermediate 2-aminomuconate (2-AM): one in fungi homologous to bacterial 2-AM deaminase, and one in metazoa homologous to prokaryotic aspartate dehydrogenase. Biochemical and structural analyses confirmed that human ASPDH has evolved a novel enzymatic function distinct from its prokaryotic ancestor, producing L-2-aminohex-3-enedioic acid, an unsaturated alpha-amino acid not previously recorded in biological databases. Isotope-labeling NMR experiments and structural modeling indicate the reaction proceeds through a mechanism coupling hydride transfer to double-bond rearrangement within a conjugated system. These findings define a new metazoan-specific branch of the kynurenine pathway, add a previously unknown amino acid to the repertoire of endogenous human metabolites, and highlight the power of comparative genomics for mapping uncharacterized reactions in human metabolism.
What's missing
As a preprint, this study has not yet undergone formal peer review. The biological role and physiological significance of the newly identified product, L-2-aminohex-3-enedioic acid, remain unknown. It is also unclear whether disruption of this newly described enzymatic step has any association with human disease or metabolic disorders. The study does not address whether ASPDH activity in this pathway varies across tissues or under different physiological conditions.
What different sources said
- bioRxivCenter
Human ASPDH is a 2-aminomuconate reductase that produces L-2-aminohex-3-enedioic acid in tryptophan catabolism
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