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Genetic diversity and function in the human cytosolic sulfotransferases
M A T Hildebrandt1, D P Carrington, B A Thomae
1Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, MN 55985, USA.
The Pharmacogenomics Journal
|June 28, 2006
Summary
Common amino-acid substitutions from nonsynonymous polymorphisms in sulfotransferase (SULT) genes rarely alter protein structure. Instead, they impact cellular interactions, making function prediction challenging.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Nonsynonymous (NS) polymorphisms lead to amino-acid substitutions that can alter protein function.
- Predicting how these substitutions affect protein function is crucial for understanding genetic variation.
- Cytosolic sulfotransferases (SULTs) are a key enzyme family involved in metabolism.
Purpose of the Study:
- To investigate the functional impact of amino-acid substitutions in SULT genes.
- To develop predictive models for variant allozyme function.
- To understand the mechanisms underlying altered protein function due to NS polymorphisms.
Main Methods:
- Gene resequencing of SULT family members.
- Functional genomics and amino-acid characterization.
- Crystal structure analysis of SULT proteins.
Main Results:
- 217 polymorphisms were identified across eight SULT genes, with 39 being nonsynonymous.
- Amino-acid changes primarily decreased immunoreactive protein levels, not enzyme kinetics.
- Neither amino-acid properties nor structural models accurately predicted variant allozyme function.
Conclusions:
- Common amino-acid substitutions in SULTs may not significantly alter protein structure.
- Altered function is likely due to uncharacterized interactions with the cellular environment.
- Predicting the functional consequences of NS polymorphisms remains a challenge.
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