Tetrahydrobiopterin regulates monoamine neurotransmitter sulfonation

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Abstract

Monoamine neurotransmitters are among the hundreds of signaling small molecules whose target interactions are switched "on" and "off" via transfer of the sulfuryl-moiety (-SO3) from PAPS (3'-phosphoadenosine 5'-phosphosulfate) to the hydroxyls and amines of their scaffolds. These transfer reactions are catalyzed by a small family of broad-specificity enzymes-the human cytosolic sulfotransferases (SULTs). The first structure of a SULT allosteric-binding site (that of SULT1A1) has recently come to light. The site is conserved among SULT1 family members and is promiscuous- it binds catechins, a naturally occurring family of flavanols. Here, the catechin-binding site of SULT1A3, which sulfonates monoamine neurotransmitters, is modeled on that of 1A1 and used to screen in silico for endogenous metabolite 1A3 allosteres. Screening predicted a single high-affinity allostere, tetrahydrobiopterin (THB), an essential cofactor in monoamine neurotransmitter biosynthesis. THB is shown to bind and inhibit SULT1A3 with high affinity, 23 (±2) nM, and to bind weakly, if at all, to the four other major SULTs found in brain and liver. The structure of the THB-bound binding site is determined and confirms that THB binds the catechin site. A structural comparison of SULT1A3 with SULT1A1 (its immediate evolutionary progenitor) reveals how SULT1A3 acquired high affinity for THB and that the majority of residue changes needed to transform 1A1 into 1A3 are clustered at the allosteric and active sites. Finally, sequence records reveal that the coevolution of these sites played an essential role in the evolution of simian neurotransmitter metabolism.

Original languageEnglish (US)
Pages (from-to)E5317-E5324
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number27
DOIs
Publication statusPublished - Jul 3 2017

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Keywords

  • Allostery
  • Evolution
  • Neurotransmitter
  • Sulfotransferase
  • Tetrahydrobiopterin

ASJC Scopus subject areas

  • General

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