Serine and Metal-Dependent meta-Cleavage Product Hydrolases

Ruzzini, Antonio C.; Kuatsjah, Eugene; Eltis, Lindsay D.

doi:10.1016/b978-0-12-409547-2.14655-4

Comprehensive Natural Products III 2020

DOI: 10.1016/b978-0-12-409547-2.14655-4

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Serine and Metal-Dependent meta-Cleavage Product Hydrolases

Antonio C. Ruzzini

Eugene Kuatsjah

Lindsay D. Eltis

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2022

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“…1 A ) ( 30 ). MCP hydrolases are serine-dependent enzymes that belong to the α/β hydrolase superfamily ( 33 ). These enzymes are ubiquitous in bacterial pathways responsible for the catabolism of alkylated aromatic compounds, hydrolyzing carbon–carbon bonds in vinylogous-1,5-diketones.…”

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confidence: 99%

The unusual convergence of steroid catabolic pathways in Mycobacterium abscessus

Crowe

Krekhno

Brown

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Mycobacterium abscessus , an opportunistic pathogen responsible for pulmonary infections, contains genes predicted to encode two steroid catabolic pathways: a cholesterol catabolic pathway similar to that of Mycobacterium tuberculosis and a 4-androstenedione (4-AD) catabolic pathway. Consistent with this prediction, M. abscessus grew on both steroids. In contrast to M. tuberculosis , Rhodococcus jostii RHA1, and other Actinobacteria, the cholesterol and 4-AD catabolic gene clusters of the M. abscessus complex lack genes encoding HsaD, the meta -cleavage product (MCP) hydrolase. However, M. abscessus ATCC 19977 harbors two hsaD homologs elsewhere in its genome. Only one of the encoded enzymes detectably transformed steroid metabolites. Among tested substrates, HsaD Mab and HsaD Mtb of M. tuberculosis had highest substrate specificities for MCPs with partially degraded side chains thioesterified with coenzyme A ( k cat / K M = 1.9 × 10 4 and 5.7 × 10 3 mM −1 s −1 , respectively). Consistent with a dual role in cholesterol and 4-AD catabolism, HsaD Mab also transformed nonthioesterified substrates efficiently, and a Δ hsaD mutant of M. abscessus grew on neither steroid. Interestingly, both steroids prevented growth of the mutant on acetate. The Δ hsaD mutant of M. abscessus excreted cholesterol metabolites with a fully degraded side chain, while the corresponding RHA1 mutant excreted metabolites with partially degraded side chains. Finally, the Δ hsaD mutant was not viable in macrophages. Overall, our data establish that the cholesterol and 4-AD catabolic pathways of M. abscessus are unique in that they converge upstream of where this occurs in characterized steroid-catabolizing bacteria. The data further indicate that cholesterol is a substrate for intracellular bacteria and that cholesterol-dependent toxicity is not strictly dependent on coenzyme A sequestration.

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mentioning

confidence: 99%

The unusual convergence of steroid catabolic pathways in Mycobacterium abscessus

Crowe

Krekhno

Brown

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Serine and Metal-Dependent meta-Cleavage Product Hydrolases

Cited by 1 publication

References 125 publications

The unusual convergence of steroid catabolic pathways in Mycobacterium abscessus

The unusual convergence of steroid catabolic pathways in Mycobacterium abscessus

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