Bacterial cysteine desulfurases: versatile key players in biosynthetic pathways of sulfur-containing biofactors

Hidese, Ryota; Mihara, Hisaaki; Esaki, Nobuyoshi

doi:10.1007/s00253-011-3336-x

Cited by 98 publications

(103 citation statements)

References 167 publications

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“…3A). We found by database searches that all the genes encoding cluster II Fdxs are adjacent to the genes putatively encoding cysteine desulfurases (54), which are involved in ISC biosynthesis (54,55), suggesting that a role of cluster II Fdxs lies in ISC biosynthesis. In human mitochondria, Fdx2 (ISC-Fdx) cannot replace the role of Fdx1 (P450-Fdx) (56).…”

Section: Discussionmentioning

confidence: 99%

Bacterial Cytochrome P450 System Catabolizing the Fusarium Toxin Deoxynivalenol

Ito

Sato

Ishizaka

et al. 2013

Appl Environ Microbiol

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c Deoxynivalenol (DON) is a natural toxin of fungi that cause Fusarium head blight disease of wheat and other small-grain cereals. DON accumulates in infected grains and promotes the spread of the infection on wheat, posing serious problems to grain production. The elucidation of DON-catabolic genes and enzymes in DON-degrading microbes will provide new approaches to decrease DON contamination. Here, we report a cytochrome P450 system capable of catabolizing DON in Sphingomonas sp. strain KSM1, a DON-utilizing bacterium newly isolated from lake water. The P450 gene ddnA was cloned through an activity-based screening of a KSM1 genomic library. The genes of its redox partner candidates (flavin adenine dinucleotide [FAD]-dependent ferredoxin reductase and mitochondrial-type [2Fe-2S] ferredoxin) were not found adjacent to ddnA; the redox partner candidates were further cloned separately based on conserved motifs. The DON-catabolic activity was reconstituted in vitro in an electron transfer chain comprising the three enzymes and NADH, with a catalytic efficiency (k cat /K m ) of 6.4 mM ؊1 s ؊1 . The reaction product was identified as 16-hydroxy-deoxynivalenol. A bioassay using wheat seedlings revealed that the hydroxylation dramatically reduced the toxicity of DON to wheat. The enzyme system showed similar catalytic efficiencies toward nivalenol and 3-acetyl deoxynivalenol, toxins that frequently cooccur with DON. These findings identify an enzyme system that catabolizes DON, leading to reduced phytotoxicity to wheat.

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Section: Discussionmentioning

confidence: 99%

Bacterial Cytochrome P450 System Catabolizing the Fusarium Toxin Deoxynivalenol

Ito

Sato

Ishizaka

et al. 2013

Appl Environ Microbiol

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“…1) (5,6). Persulfides readily react with oxidants, so the active site of SufS is more buried as compared with housekeeping cysteine desulfurases such as IscS (7). The monomeric 15.8-kDa SufE co-substrate protein interacts with the SufS dimer to stimulate cysteine desulfurase activity and accepts sulfane sulfur through a persulfide transfer reaction (8,9).…”

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confidence: 99%

Escherichia coli SufE Sulfur Transfer Protein Modulates the SufS Cysteine Desulfurase through Allosteric Conformational Dynamics

Singh

Dai

Outten

et al. 2013

Journal of Biological Chemistry

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Background: SufS cysteine desulfurase mobilizes sulfur for stress-responsive iron-sulfur cluster biogenesis in bacteria. Results: Interaction with the sulfur transfer protein SufE triggers conformational changes in the SufS active site. Conclusion: SufE participates in allosteric regulation of SufS activity in addition to being a sulfur acceptor. Significance: New insight into sulfur mobilization and transfer during iron-sulfur cluster metallocofactor assembly is provided.

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“…1 and 3) with similar k cat /K m values ( Table 1). The observed K m values of LnmJ-SH, CaJ-SH, and MaJ-SH with all tested substrates (1)(2)(3)(4)(5)(6)(7)(8)(9)(10) are between 1.9 ± 0.2 and 42 ± 6 mM (Table 1), which are too high to be relevant under the physiological reactions. These high K m values may result from the structural difference between the native substrates of the SH domains and the substrate mimics tested, the fact that the SH domains were studied in isolation (i.e., in truncation lacking the context of other domains within the native PKS modules), or a combination of both (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…Sulfur-containing metabolites are well known from both primary and secondary metabolism (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The best-characterized sulfur-incorporating enzymes from primary metabolism include the following: (i) the group I and II cysteine desulfurases that use L-cysteine as the substrate and catalyze the production of a protein-bound persulfide and alanine, as exemplified by NifS, IscC, and CsdB (1-3); (ii) the D-cysteine desulfhydrases that use D-cysteine as the substrate and catalyze the β-elimination reaction to produce hydrogen sulfide, ammonia, and pyruvate (32); and (iii) the cysteine S-conjugate β-lyases that use L-cysteine-S-conjugates as the substrates and catalyze the β-elimination reaction to produce a thiol, ammonia, and pyruvate (33).…”

Section: Discussionmentioning

confidence: 99%

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C-S bond cleavage by a polyketide synthase domain

Lohman

Liu

et al. 2015

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

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Leinamycin (LNM) is a sulfur-containing antitumor antibiotic featuring an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. The 1,3-dioxo-1,2-dithiolane moiety is essential for LNM's antitumor activity, by virtue of its ability to generate an episulfonium ion intermediate capable of alkylating DNA. We have previously cloned and sequenced the lnm gene cluster from Streptomyces atroolivaceus S-140. In vivo and in vitro characterizations of the LNM biosynthetic machinery have since established that: (i) the 18-membered macrolactam backbone is synthesized by LnmP, LnmQ, LnmJ, LnmI, and LnmG, (ii) the alkyl branch at C-3 of LNM is installed by LnmK, LnmL, LnmM, and LnmF, and (iii) leinamycin E1 (LNM E1), bearing a thiol moiety at C-3, is the nascent product of the LNM hybrid nonribosomal peptide synthetase (NRPS)-acyltransferase (AT)-less type I polyketide synthase (PKS). Sulfur incorporation at C-3 of LNM E1, however, has not been addressed. Here we report that: (i) the bioinformatics analysis reveals a pyridoxal phosphate (PLP)-dependent domain, we termed cysteine lyase (SH) domain (LnmJ-SH), within PKS module-8 of LnmJ; (ii) the LnmJ-SH domain catalyzes C-S bond cleavage by using L-cysteine and L-cysteine S-modified analogs as substrates through a PLP-dependent β-elimination reaction, establishing L-cysteine as the origin of sulfur at C-3 of LNM; and (iii) the LnmJ-SH domain, sharing no sequence homology with any other enzymes catalyzing C-S bond cleavage, represents a new family of PKS domains that expands the chemistry and enzymology of PKSs and might be exploited to incorporate sulfur into polyketide natural products by PKS engineering.cysteine metabolism | enzyme mechanism | genome mining | pathway engineering | sulfur metabolism S ulfur is found in many primary metabolites, such as thiamin, biotin, molybdenum cofactors, lipoic acid, iron-sulfur clusters, and nucleosides including 2-thiocytidine, 4-thiouridine, and 2-methylthio-N 6 -isopentenyl adenosine (1). There is a wealth of information on how sulfur is incorporated into these primary metabolites, the key step of which is catalyzed by a desulfurase to produce a protein-bound cysteine persulfide by using cysteine as a substrate (2-5). Sulfur is also found in many secondary metabolites (interchangeably referred to as natural products here). The major groups of sulfur-containing natural products are peptides produced by ribosome or nonribosomal peptide synthetases (NRPSs). Sulfur incorporation into these natural products from intact cysteine or methionine is well characterized. However, sulfur incorporation into other natural products remains poorly understood. Only a few cases featured by C-S bond formation or C-S bond cleavage steps were reported to date, and most of the mechanisms require further investigation (6-15).Leinamycin (LNM) is a sulfur-containing antitumor antibiotic produced by Streptomyces atroolivaceus S-140 (16). The structure of LNM is characterized by an unusual 1,3-dioxo-1,2-dith...

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Bacterial cysteine desulfurases: versatile key players in biosynthetic pathways of sulfur-containing biofactors

Cited by 98 publications

References 167 publications

Bacterial Cytochrome P450 System Catabolizing the Fusarium Toxin Deoxynivalenol

Bacterial Cytochrome P450 System Catabolizing the Fusarium Toxin Deoxynivalenol

Escherichia coli SufE Sulfur Transfer Protein Modulates the SufS Cysteine Desulfurase through Allosteric Conformational Dynamics

C-S bond cleavage by a polyketide synthase domain

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