A common polymorphic variant of UGT1A5 displays increased activity due to optimized cofactor binding

Area of Science:

• Biochemistry
• Pharmacology
• Enzymology

Background:

• Uridine diphosphate-glucuronosyltransferases (UGTs) are critical phase II drug-metabolizing enzymes in humans.
• Understanding UGT enzyme function and variability is crucial for predicting drug efficacy and toxicity.

Discussion:

• This study demonstrates UGT1A5's capability to perform N-glucuronidation using a novel fission yeast cell system.
• Two novel polymorphic UGT1A5 variants, UGT1A5*8 and UGT1A5*9, were identified and characterized.
• UGT1A5*8 exhibits significantly increased enzyme activity compared to wild-type, while UGT1A5*9 shows similar activity.

Key Insights:

• Molecular modeling and dynamics simulations pinpoint the Gly259Arg mutation in UGT1A5*8 as the cause of enhanced activity.
• The Gly259Arg mutation stabilizes helix Q, optimizing cofactor geometry for improved catalytic function.
• The location of mutations relative to the substrate-binding site explains the varying impact on enzyme activity.

Outlook:

• Further investigation into UGT1A5 polymorphisms can refine drug metabolism predictions.
• This research provides a foundation for understanding enzyme kinetics and developing personalized medicine approaches.
• The fission yeast 'enzyme bag' system offers a versatile platform for studying other drug-metabolizing enzymes.