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Literature summary extracted from

  • Shi, Y.; Colombo, C.; Kuttiyatveetil, J.R.; Zalatar, N.; van Straaten, K.E.; Mohan, S.; Sanders, D.A.; Pinto, B.M.
    A second, druggable binding site in UDP-galactopyranose mutase from Mycobacterium tuberculosis? (2016), ChemBioChem, 17, 2264-2273 .
    View publication on PubMed

Application

EC Number Application Comment Organism
5.4.99.9 drug development UDP-galactopyranose mutase (UGM), a key enzyme in the biosynthesis of mycobacterial cell walls, is a potential target for the treatment of tuberculosis Mycobacterium tuberculosis

Protein Variants

EC Number Protein Variants Comment Organism
5.4.99.9 D322A site-directed mutagenesis, the mutant shows altered kinetics compared to the wild-type with substrate UDP-alpha-D-galactofuranose Mycobacterium tuberculosis
5.4.99.9 Y253A site-directed mutagenesis, the mutant shows altered kinetics compared to the wild-type with substrate UDP-alpha-D-galactofuranose Mycobacterium tuberculosis

Inhibitors

EC Number Inhibitors Comment Organism Structure
5.4.99.9 (4-chlorophenyl)(1-(4-chlorophenyl)-5-hydroxy-1H-pyrazol-4-yl)methanone i.e. MS-208, a non-substrate-like inhibitor, mixed inhibition due to a lack of direct competition between MS-208 and the enzyme substrate. Molecular dynamics studies reveal that the MS-208 inhibition occurs by preventing complete closure of an active site mobile loop that is necessary for productive substrate binding. The results suggest the presence of an A-site with potential druggability. Kinetic analysis, docking, and molecular dynamics simulation and modeling of enzyme binding, overview. Model of the tertiary complex MtUGM:UDP-Galp:MS-208. Two A-loop residues, Glu321 and Asp322, are stabilized by MS-208 binding yet destabilized by UDP-Galp binding, with the former effect being more pronounced Mycobacterium tuberculosis
5.4.99.9 additional information modeling of binding of substrate-like inhibitors using enzyme crystal structures, PDB IDs 1V0J and 4RPH. Modeling of non-substrate-like inhibitors using an integrated approach that combines saturation transfer difference (STD) NMR spectroscopy, enzyme kinetic assays, molecular modeling, and mutagenesis, leading to the discovery of a second binding site, distinct from the enzyme active site, to which (4-chlorophenyl)(1-(4-chlorophenyl)-5-hydroxy-1H-pyrazol-4-yl)methanone binds, affecting productive substrate binding at the active site and inhibiting enzyme function. Competition STD NMR experiments Mycobacterium tuberculosis

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
5.4.99.9 additional information
-
 additional information Michaelis-Menten kinetics of wild-type and mutant enzymes Mycobacterium tuberculosis

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
5.4.99.9 UDP-alpha-D-galactopyranose Mycobacterium tuberculosis
-
 UDP-alpha-D-galactofuranose
-
 r

Organism

EC Number Organism UniProt Comment Textmining
5.4.99.9 Mycobacterium tuberculosis
-
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
5.4.99.9 UDP-alpha-D-galactofuranose UGM-catalyzed interconversion Mycobacterium tuberculosis UDP-alpha-D-galactopyranose
-
 r
5.4.99.9 UDP-alpha-D-galactopyranose
-
 Mycobacterium tuberculosis UDP-alpha-D-galactofuranose
-
 r
5.4.99.9 UDP-alpha-D-galactopyranose UGM-catalyzed interconversion Mycobacterium tuberculosis UDP-alpha-D-galactofuranose
-
 r

Synonyms

EC Number Synonyms Comment Organism
5.4.99.9 MtUGM
-
 Mycobacterium tuberculosis
5.4.99.9 UGM
-
 Mycobacterium tuberculosis

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
5.4.99.9 37
-
 assay at Mycobacterium tuberculosis

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
5.4.99.9 7.6
-
 assay at Mycobacterium tuberculosis

Cofactor

EC Number Cofactor Comment Organism Structure
5.4.99.9 FAD FADH- Mycobacterium tuberculosis

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
5.4.99.9 additional information
-
 additional information inhibition kinetic analysis Mycobacterium tuberculosis

General Information

EC Number General Information Comment Organism
5.4.99.9 physiological function UDP-galactopyranose mutase (UGM) is a key enzyme in the biosynthesis of mycobacterial cell walls. Galactofuranose (Galf) is an essential building block of the galactan chains in the cell walls of mycobacteria Mycobacterium tuberculosis