Tématerületi Kiválósági Program 2021(NKFI TKP2021-EGA-23) Támogató: NKFI
Sulfotransferases (SULTs) are phase II metabolizing enzymes catalyzing the sulfoconjugation
from the co-factor 3′-Phosphoadenosine 5′-Phosphosulfate (PAPS) to a wide variety
of endogenous compounds, drugs and natural products. Although SULT1A1 and SULT1A3
share 93% identity, SULT1A1, the most abundant SULT isoform in humans, exhibits a
broad substrate range with specificity for small phenolic compounds, while SULT1A3
displays a high affinity toward monoamine neurotransmitters like dopamine. To elucidate
the factors determining the substrate specificity of the SULT1 isoenzymes, we studied
the dynamic behavior and structural specificities of SULT1A1 and SULT1A3 by using
molecular dynamics (MD) simulations and ensemble docking of common and specific substrates
of the two isoforms. Our results demonstrated that while SULT1A1 exhibits a relatively
rigid structure by showing lower conformational flexibility except for the lip (loop
L1), the loop L2 and the cap (L3) of SULT1A3 are extremely flexible. We identified
protein residues strongly involved in the recognition of different substrates for
the two isoforms. Our analyses indicated that being more specific and highly flexible,
the structure of SULT1A3 has particularities in the binding site, which are crucial
for its substrate selectivity.
