Conformational diversity defines substrate specificity of thymidylate/uridylate kinase from Candida albicans

Thymidylate kinase (TMK) from Candida albicans (CaTMK) contains a unique 15 residue insert, the CaLoop, that is not found on other TMKs. CaTMK is proficient at phosphorylating deoxyuridine monophosphate (dUMP), showing a rate 6-fold higher than TMP. It has been shown that deletion of the CaLoop redu...

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Bibliographic Details
Published in:Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2021-08, Vol.89 (8), p.937-944
Main Authors: Sinha, Kaustubh, Rule, Gordon S
Format: Article
Language:English
Subjects:
Candida albicans
Deletion
Enzymes
Kinases
Molecular dynamics
Protein structure
Substrate specificity
Substrates
Uridylate kinase
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Summary:Thymidylate kinase (TMK) from Candida albicans (CaTMK) contains a unique 15 residue insert, the CaLoop, that is not found on other TMKs. CaTMK is proficient at phosphorylating deoxyuridine monophosphate (dUMP), showing a rate 6-fold higher than TMP. It has been shown that deletion of the CaLoop reduces the activity towards dUMP by 19-fold, but has only a modest 4-fold decrease in activity towards TMP. The molecular dynamics calculations presented here show that the increased activity towards dUMP is due to an increase in flexibility and correlated motions of the protein that allows the enzyme-dUMP complex to more readily approach a catalytically competent state. Deletion of the CaLoop allows the dUMP-enzyme complex to adopt catalytically non-functional conformations. In contrast, TMP stabilizes the deletion such that it remains in a functional conformation that is similar to the conformation of the original enzyme.
ISSN:0887-3585
1097-0134
DOI:10.1002/prot.26071