ArticleBiochemistry2012
Crystal structures of Trypanosoma cruzi UDP-galactopyranose mutase implicate flexibility of the histidine loop in enzyme activation.
Article in Biochemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- Glycocalyx-Driven Immunomodulation in Trypanosoma cruzi: Structures, Host Responses, Diagnostic and Therapeutic Targeting.Parasite immunology · 2026Review
- Structural bioinformatics insights into UDP-galactopyranose mutase (UGM) as a novel drug target for antifilarial therapy against human filarial parasite Brugia malayi.Molecular diversity · 2026Article
- The Glycan Structure ofMolecules (Basel, Switzerland) · 2020Review
- N5 Is the New C4a: Biochemical Functionalization of Reduced Flavins at the N5 Position.Frontiers in molecular biosciences · 2020Review
- Molecular Dynamics Simulations of Substrate Release from Trypanosoma cruzi UDP-Galactopyranose Mutase.Journal of chemical information and modeling · 2019Article
- Steric Control of the Rate-Limiting Step of UDP-Galactopyranose Mutase.Biochemistry · 2018Article
- Multiple functionalities of reduced flavin in the non-redox reaction catalyzed by UDP-galactopyranose mutase.Archives of biochemistry and biophysics · 2017Review
- Conformational Control of UDP-Galactopyranose Mutase Inhibition.Biochemistry · 2017Article
- The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations.Molecules (Basel, Switzerland) · 2016Review
- In Crystallo Capture of a Covalent Intermediate in the UDP-Galactopyranose Mutase Reaction.Biochemistry · 2016Article
- Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents.ACS chemical biology · 2015Article
- Contributions of unique active site residues of eukaryotic UDP-galactopyranose mutases to substrate recognition and active site dynamics.Biochemistry · 2014Article
- Structure, mechanism, and dynamics of UDP-galactopyranose mutase.Archives of biochemistry and biophysics · 2014Review
- Article
- Substrate-dependent dynamics of UDP-galactopyranose mutase: Implications for drug design.Protein science : a publication of the Protein Society · 2013Article
- UDP-galactopyranose mutases from Leishmania species that cause visceral and cutaneous leishmaniasis.Archives of biochemistry and biophysics · 2013Article
- Noncanonical reactions of flavoenzymes.International journal of molecular sciences · 2012Review
- Identification of the NAD(P)H binding site of eukaryotic UDP-galactopyranose mutase.Journal of the American Chemical Society · 2012Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. Here we report crystal structures of the galactofuranose biosynthetic enzyme UDP-galactopyranose mutase (UGM) from T. cruzi, which are the first structures of this enzyme from a protozoan parasite. UGM is an attractive target for drug design because galactofuranose is absent in humans but is an essential component of key glycoproteins and glycolipids in trypanosomatids. Analysis of the enzyme-UDP noncovalent interactions and sequence alignments suggests that substrate recognition is exquisitely conserved among eukaryotic UGMs and distinct from that of bacterial UGMs. This observation has implications for inhibitor design. Activation of the enzyme via reduction of the FAD induces profound conformational changes, including a 2.3 Å movement of the histidine loop (Gly60-Gly61-His62), rotation and protonation of the imidazole of His62, and cooperative movement of residues located on the si face of the FAD. Interestingly, these changes are substantially different from those described for Aspergillus fumigatus UGM, which is 45% identical to T. cruzi UGM. The importance of Gly61 and His62 for enzymatic activity was studied with the site-directed mutant enzymes G61A, G61P, and H62A. These mutations lower the catalytic efficiency by factors of 10-50, primarily by decreasing k(cat). Considered together, the structural, kinetic, and sequence data suggest that the middle Gly of the histidine loop imparts flexibility that is essential for activation of eukaryotic UGMs. Our results provide new information about UGM biochemistry and suggest a unified strategy for designing inhibitors of UGMs from the eukaryotic pathogens.
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