Semisynthesis of the Organoarsenical Antibiotic Arsinothricin.
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ABSTRACT:
SUBMITTER: Suzol SH
PROVIDER: S-EPMC7867689 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Arsenic is the most pervasive environmental toxic substance. As a consequence of its ubiquity, nearly every organism has genes for resistance to inorganic arsenic. In bacteria these genes are found largely in bacterial arsenic resistance (ars) operons. Recently a parallel pathway for synthesis and degradation of methylated arsenicals has been identified. The arsM gene product encodes the ArsM (AS3MT in animals) As(iii) S-adenosylmethionine methyltransferase that methylates inorganic trivalent arsenite in three sequential steps to methylarsenite MAs(iii), dimethylarsenite (DMAs(iii) and trimethylarsenite (TMAs(iii)). MAs(iii) is considerably more toxic than As(iii), and we have proposed that MAs(iii) was a primordial antibiotic. Under aerobic conditions these products are oxidized to nontoxic pentavalent arsenicals, so that methylation became a detoxifying pathway after the atmosphere became oxidizing. Other microbes have acquired the ability to regenerate MAs(v) by reduction, transforming it again into toxic MAs(iii). Under this environmental pressure, MAs(iii) resistances evolved, including the arsI, arsH and arsP genes. ArsI is a C-As bond lyase that demethylates MAs(iii) back to less toxic As(iii). ArsH re-oxidizes MAs(iii) to MAs(v). ArsP actively extrudes MAs(iii) from cells. These proteins confer resistance to this primitive antibiotic. This oscillation between MAs(iii) synthesis and detoxification is an essential component of the arsenic biogeocycle.
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Project description:The soil bacterium Burkholderia gladioli GSRB05 produces the natural compound arsinothricin [2-amino-4-(hydroxymethylarsinoyl) butanoate] (AST), which has been demonstrated to be a broad-spectrum antibiotic. To identify the genes responsible for AST biosynthesis, a draft genome sequence of B. gladioli GSRB05 was constructed. Three genes, arsQML, in an arsenic resistance operon were found to be a biosynthetic gene cluster responsible for synthesis of AST and its precursor, hydroxyarsinothricin [2-amino-4-(dihydroxyarsinoyl) butanoate] (AST-OH). The arsL gene product is a noncanonical radical S-adenosylmethionine (SAM) enzyme that is predicted to transfer the 3-amino-3-carboxypropyl (ACP) group from SAM to the arsenic atom in inorganic arsenite, forming AST-OH, which is methylated by the arsM gene product, a SAM methyltransferase, to produce AST. Finally, the arsQ gene product is an efflux permease that extrudes AST from the cells, a common final step in antibiotic-producing bacteria. Elucidation of the biosynthetic gene cluster for this novel arsenic-containing antibiotic adds an important new tool for continuation of the antibiotic era. IMPORTANCE Antimicrobial resistance is an emerging global public health crisis, calling for urgent development of novel potent antibiotics. We propose that arsinothricin and related arsenic-containing compounds may be the progenitors of a new class of antibiotics to extend our antibiotic era. Here, we report identification of the biosynthetic gene cluster for arsinothricin and demonstrate that only three genes, two of which are novel, are required for the biosynthesis and transport of arsinothricin, in contrast to the phosphonate counterpart, phosphinothricin, which requires over 20 genes. Our discoveries will provide insight for the development of more effective organoarsenical antibiotics and illustrate the previously unknown complexity of the arsenic biogeochemical cycle, as well as bring new perspective to environmental arsenic biochemistry.
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