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9f69

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Crystal structure of human triose phosphate isomerase with methyl malonic acid ligand

Structural highlights

9f69 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.17Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TPIS_HUMAN Defects in TPI1 are the cause of triosephosphate isomerase deficiency (TPI deficiency) [MIM:190450. TPI deficiency is an autosomal recessive disorder. It is the most severe clinical disorder of glycolysis. It is associated with neonatal jaundice, chronic hemolytic anemia, progressive neuromuscular dysfunction, cardiomyopathy and increased susceptibility to infection.

Function

TPIS_HUMAN

Publication Abstract from PubMed

Modulation of enzyme activity by metabolites represents the most efficient and rapid way of controlling metabolism. Investigating enzyme-metabolite interactions can deepen our understanding of metabolic control and aid in identifying enzyme modulators with potential therapeutic applications. These interactions vary in strength, with dissociation constants (K(d)) ranging from strong (nm) to weak (mum-mm). However, weak interactions are often overlooked due to the challenges in studying them. Despite this, weak modulators can reveal unknown binding modes and serve as starting points for compound optimization. In this study, we aimed to identify metabolites that weakly modulate the activity of human glucose-6-phosphate isomerase (GPI) and triosephosphate isomerase (TPI), which are potential therapeutic targets in tumor glycolysis. Through a combination of activity and binding assays, the screening revealed multiple weak inhibitors for the two targets, causing partial attenuation of their activity, with K(d) and K(i) in the low mm range. X-ray crystallography revealed six orthosteric ligands binding to the active sites - four inhibitors of GPI and two of TPI. Our findings underscore the role of weak interactions in enzyme regulation and may provide structural insights that could aid the design of inhibitors targeting human GPI and TPI in cancer intervention.

Human glycolysis isomerases are inhibited by weak metabolite modulators.,Jonatansdottir YY, Rolfsson O, Hjorleifsson JG FEBS J. 2025 Feb 27. doi: 10.1111/febs.70049. PMID:40014465^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Jónatansdóttir YY, Rolfsson Ó, Hjörleifsson JG. Human glycolysis isomerases are inhibited by weak metabolite modulators. FEBS J. 2025 Feb 27. PMID:40014465 doi:10.1111/febs.70049