Biosynthesis of a Central Intermediate in Hydrogen
Sulfide Metabolism by a Novel Human Sulfurtransferase and Its Yeast
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Abstract
Human sulfide:quinone oxidoreductase
(SQOR) catalyzes the conversion
of H<sub>2</sub>S to thiosulfate, the first step in mammalian H<sub>2</sub>S metabolism. SQOR’s inability to produce the glutathione
persulfide (GSS<sup>–</sup>) substrate for sulfur dioxygenase
(SDO) suggested that a thiosulfate:glutathione sulfurtransferase (TST)
was required to provide the missing link between the SQOR and SDO
reactions. Although TST could be purified from yeast, attempts to
isolate the mammalian enzyme were not successful. We used bioinformatic
approaches to identify genes likely to encode human TST (<i>TSTD1</i>) and its yeast ortholog (<i>RDL1</i>). Recombinant TSTD1
and RDL1 catalyze a predicted thiosulfate-dependent conversion of
glutathione to GSS<sup>–</sup>. Both enzymes contain a rhodanese
homology domain and a single catalytically essential cysteine, which
is converted to cysteine persulfide upon reaction with thiosulfate.
GSS<sup>–</sup> is a potent inhibitor of TSTD1 and RDL1, as
judged by initial rate accelerations and ≥25-fold lower <i>K</i><sub>m</sub> values for glutathione observed in the presence
of SDO. The combined action of GSS<sup>–</sup> and SDO is likely
to regulate the biosynthesis of the reactive metabolite. SDO drives
to completion <i>p</i>-toluenethiosulfonate:glutathione
sulfurtransferase reactions catalyzed by TSTD1 and RDL1. The thermodynamic
coupling of the irreversible SDO and reversible TST reactions provides
a model for the physiologically relevant reaction with thiosulfate
as the sulfane donor. The discovery of bacterial Rosetta Stone proteins
that comprise fusions of SDO and TSTD1 provides phylogenetic evidence
of the association of these enzymes. The presence of adjacent bacterial
genes encoding SDO–TSTD1 fusion proteins and human-like SQORs
suggests these prokaryotes and mammals exhibit strikingly similar
pathways for H<sub>2</sub>S metabolism