Does SULT2A1 convert DHEA to DHEA-S and influence circulating DHEA-S levels?

Dehydroepiandrosterone sulfate (DHEA-S) is the most abundant circulating steroid in humans, serving as a critical reservoir for active androgens and estrogens. Its production naturally declines with age, making the genetic and enzymatic regulators of its synthesis highly relevant for aging populations.

Mechanistic pathways of sulfonation

• Enzymatic conversion: The SULT2A1 gene encodes the cytosolic hydroxysteroid sulfotransferase (adrenal sulfotransferase), which is highly concentrated in the liver and the zona reticularis of the adrenal cortex.
• Sulfate donation: SULT2A1 catalyzes the transfer of a sulfonate group to the 3β-hydroxyl group of DHEA to form DHEA-S. This process requires the essential sulfate donor PAPS, which is supplied by the PAPSS2 enzyme.
• Kinetics: SULT2A1 exhibits a low-micromolar affinity ($K_m$) for DHEA, but high substrate concentrations can trigger substrate inhibition through the formation of dead-end ternary complexes.

Genetic influence on circulating levels

• GWAS validation: A large genome-wide association study of 14,846 individuals identified the single nucleotide polymorphism (SNP) rs2637125, located near SULT2A1, as a genome-wide significant locus ($P = 2.61 \times 10^{-19}$) associated with circulating DHEA-S levels. Carrying the minor allele of rs2637125 is linked to lower serum DHEA-S concentrations (beta $\approx$ -0.09).
• Alternative variants and structure: Other variants, such as rs182420, and structural copy number variations (CNVs) in the SULT2A1 locus significantly alter DHEA-S output, with higher gene copy numbers corresponding to elevated baseline excretion.

Bottom line

• The SULT2A1 gene encodes the primary enzyme responsible for converting DHEA to its sulfated reservoir form, DHEA-S, in a process dependent on PAPSS2-derived PAPS. Common genetic variations, particularly the rs2637125 SNP and structural copy number variations, directly modulate circulating DHEA-S concentrations.