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Published on: May 3, 2021
Structure, dynamics and selectivity in the sulfotransferase family
Thomas S Leyh1, Ian Cook, Ting Wang
1Department of Microbiology and Immunology, Albert Einstein College of Medicine , Bronx, NY , USA.
Drug Metabolism Reviews
|September 13, 2013
Summary
Human cytosolic sulfotransferases (SULTs) utilize an active-site cap mechanism, controlled by the binding of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), to regulate substrate access and selectivity for metabolic functions.
Area of Science:
- Biochemistry
- Enzymology
- Structural Biology
Background:
- Human cytosolic sulfotransferases (SULT1A1 and SULT2A1) are key metabolic enzymes.
- These enzymes possess a dynamic active-site cap structure that influences substrate interactions.
Purpose of the Study:
- To investigate the role of the active-site cap in regulating substrate access and selectivity.
- To elucidate the mechanism by which 3 '-phosphoadenosine 5 '-phosphosulfate (PAPS) binding affects enzyme conformation and function.
Main Methods:
- Combined structure, function, and molecular dynamics studies.
- Analysis of enzyme states (open and closed pores) based on PAPS binding.
Main Results:
- The active-site cap undergoes conformational changes upon PAPS binding, gating access to the enzyme's active site.
- The enzyme exists predominantly in a constricted state (≈95%) when PAPS is bound, with pore isomerization occurring.
- Distinct pore dimensions in open and closed states impose different steric constraints, enabling dual specificity settings.
Conclusions:
- The cap mechanism provides two specificity settings (closed-pore and open-pore) matched to SULT metabolic demands.
- Nucleotide release triggers cap opening, explaining observed product bursts and substrate inhibition in SULTs.
- This mechanism offers advantages for enzyme function within the cellular metabolic environment.
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