Abstract
Sulfonucleotide reductases are a diverse family of enzymes that catalyze the first committed step of reductive sulfur assimilation. In this reaction, activated sulfate in the context of adenosine-5′-phosphosulfate (APS) or 3′-phosphoadenosine 5′-phosphosulfate (PAPS) is converted to sulfite with reducing equivalents from thioredoxin. The sulfite generated in this reaction is utilized in bacteria and plants for the eventual production of essential biomolecules such as cysteine and coenzyme A. Humans do not possess a homologous metabolic pathway, and thus, these enzymes represent attractive targets for therapeutic intervention. Here we studied the mechanism of sulfonucleotide reduction by APS reductase from the human pathogen Mycobacterium tuberculosis, using a combination of mass spectrometry and biochemical approaches. The results support the hypothesis of a two-step mechanism in which the sulfonucleotide first undergoes rapid nucleophilic attack to form an enzyme-thiosulfonate (E-Cys-S-SO3 −) intermediate. Sulfite is then released in a thioredoxin-dependent manner. Other sulfonucleotide reductases from structurally divergent subclasses appear to use the same mechanism, suggesting that this family of enzymes has evolved from a common ancestor.
Highlights
Carbon, nitrogen, and sulfur undergo energy cycles in our environment that are essential to support life
The evolutionary relatedness within the family of sulfonucleotide reductases has been strongly suggested by sequence homology
the general mechanism of sulfonucleotide reduction established in this work revalidates the evolutionarily relatedness of these enzymes
Summary
Nitrogen, and sulfur undergo energy cycles in our environment that are essential to support life. While carbon and nitrogen are available primarily as gases that require fixation, sulfur occurs abundantly as inorganic sulfate Despite this apparent advantage, a substantial energetic hurdle must still be overcome to convert the sulfur in its most oxidized form into sulfide, the oxidation state of sulfur required for the synthesis of essential biomolecules [1]. A substantial energetic hurdle must still be overcome to convert the sulfur in its most oxidized form into sulfide, the oxidation state of sulfur required for the synthesis of essential biomolecules [1] This transformation is accomplished by a group of enzymes that, together, make up the sulfate assimilation pathway [2]. The resulting compound, adenosine 59-phosphosulfate (APS), contains a unique high-energy anhydride bond This vital intermediate resides at a metabolic hub within M. tuberculosis. For the purposes of thiol or sulfide-containing metabolite production mentioned above, APS is shuttled through the reductive branch of this pathway (Figure 1, reactions c1, d, and e)
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