Consecutive Enzymatic Modification of Ornithine Generates the Hydroxamate Moieties of the Siderophore Erythrochelin

Robbel, Lars; Helmetag, Verena; Knappe, Thomas A.; Marahiel, Mohamed A.

doi:10.1021/bi200699x

Cited by 22 publications

(34 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of interest, our results support the recent suggestion that MCD may be a bifunctional enzyme that also acts as an acetylase regulating protein acetylation (16). However, our findings do not confirm whether MCD acts as an acetylase itself or simply controls protein acetylation via controlling acetyl CoA content (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 57%

See 1 more Smart Citation

Genetic and Pharmacological Inhibition of Malonyl CoA Decarboxylase Does Not Exacerbate Age-Related Insulin Resistance in Mice

et al. 2016

View full text Add to dashboard Cite

Aging is associated with the development of chronic diseases such as insulin resistance and type 2 diabetes. A reduction in mitochondrial fat oxidation is postulated to be a key factor contributing to the progression of these diseases. Our aim was to investigate the contribution of impaired mitochondrial fat oxidation toward age-related disease. Mice deficient for malonyl CoA decarboxylase (MCD 2/2 ), a mouse model of reduced fat oxidation, were allowed to age while life span and a number of physiological parameters (glucose tolerance, insulin tolerance, indirect calorimetry) were assessed. Decreased fat oxidation in MCD 2/2 mice resulted in the accumulation of lipid intermediates in peripheral tissues, but this was not associated with a worsening of age-associated insulin resistance and, conversely, improved longevity. This improvement was associated with reduced oxidative stress and reduced acetylation of the antioxidant enzyme superoxide dismutase 2 in muscle but not the liver of MCD 2/2 mice. These findings were recapitulated in aged mice treated with an MCD inhibitor (CBM-3001106), and these mice also demonstrated improvements in glucose and insulin tolerance. Therefore, our results demonstrate that in addition to decreasing fat oxidation, MCD inhibition also has novel effects on protein acetylation. These combined effects protect against age-related metabolic dysfunction, demonstrating that MCD inhibitors may have utility in the battle against chronic disease in the elderly.

show abstract

Section: Discussionsupporting

confidence: 57%

“…Recent studies have suggested that in addition to controlling fatty acid oxidation rates via malonyl CoA, MCD may also function as an acetylase (16). In support of this, similar to SOD2 acetylation, overall protein acetylation was Fig.…”

Section: Inhibition Decreases Muscle Acetylation and Improves Agementioning

confidence: 72%

Genetic and Pharmacological Inhibition of Malonyl CoA Decarboxylase Does Not Exacerbate Age-Related Insulin Resistance in Mice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Furthermore, MbtG homologs involved in N 5 -hydroxylation of L-ornithine catalyze hydroxylation on the free amino acid prior to incorporation by the associated NRPS (25). Finally, a similar progression of N 5 acylation followed by N 5 hydroxylation of L-ornithine occurs during erythrochelin biosynthesis (32). Based on our data and these precedents, it is reasonable to conclude that L-Lys modification in MBT biosynthesis proceeds as follows: (Fig.…”

supporting

confidence: 64%

Analyses of MbtB, MbtE, and MbtF Suggest Revisions to the Mycobactin Biosynthesis Pathway in Mycobacterium tuberculosis

2012

View full text Add to dashboard Cite

The production of mycobactin (MBT) by Mycobacterium tuberculosis is essential for this bacterium to access iron when it is in an infected host. Due to this essential function, there is considerable interest in deciphering the mechanism of MBT assembly, with the goal of targeting select biosynthetic steps for antituberculosis drug development. The proposed scheme for MBT biosynthesis involves assembly of the MBT backbone by a hybrid nonribosomal peptide synthetase (NRPS)/polyketide synthase (PKS) megasynthase followed by the tailoring of this backbone by N 6 acylation of the central l -Lys residue and subsequent N 6 -hydroxylation of the central N 6 -acyl- l -Lys and the terminal caprolactam. A complete testing of this hypothesis has been hindered by the inability to heterologously produce soluble megasynthase components. Here we show that soluble forms of the NRPS components MbtB, MbtE, and MbtF are obtained when these enzymes are coproduced with MbtH. Using these soluble enzymes we determined the amino acid specificity of each adenylation (A) domain. These results suggest that the proposed tailoring enzymes are actually involved in precursor biosynthesis since the A domains of MbtE and MbtF are specific for N 6 -acyl- N 6 -hydroxy- l -Lys and N 6 -hydroxy- l -Lys, respectively. Furthermore, the preference of the A domain of MbtB for l -Thr over l -Ser suggests that the megasynthase produces MBT derivatives with β-methyl oxazoline rings. Since the most prominent form of MBT produced by M. tuberculosis lacks this β-methyl group, a mechanism for demethylation remains to be discovered. These results suggest revisions to the MBT biosynthesis pathway while also identifying new targets for antituberculosis drug development.

show abstract

“…The other possibility previously entertained was that NocA was not essential and an alternate starting module existed, as in anabaenopeptin biosynthesis in Anabaena [39], encoded in a yet unknown gene cluster but capable of ‘crosstalking’ with the nocardicin gene cluster. Cross talk between gene clusters has been observed in the biosynthesis of erythrochelin [40, 41] and rhodochelin [42]. …”

Section: Resultsmentioning

confidence: 99%

In Vivo Characterization of Nonribosomal Peptide Synthetases NocA and NocB in the Biosynthesis of Nocardicin A

Davidsen

Townsend

2012

Chemistry & Biology

View full text Add to dashboard Cite

SUMMARY Two non-ribosomal peptide synthetases (NRPS), NocA and NocB, together comprising 5 modules, are essential for the biosynthesis of the D,L,D configured tripeptide backbone of the monocyclic β-lactam nocardicin A. We report a double replacement gene strategy in which point mutations were engineered in the two encoding NRPS genes without disruption of the nocABC operon by placing selective markers in adjacent genes. A series of mutants was constructed to inactivate the thiolation (T) domain of each module, evaluate an HHxxxDR catalytic motif in NocA and an atypical extended histidine motif in NocB. The loss of nocardicin A production in each of the T domain mutants indicates all 5 modules are essential for its biosynthesis. Conversely, production of nocardicin A production was not affected by mutation of the NocB histidine motif or the R828G mutation in NocA.

show abstract

Consecutive Enzymatic Modification of Ornithine Generates the Hydroxamate Moieties of the Siderophore Erythrochelin

Cited by 22 publications

References 33 publications

Genetic and Pharmacological Inhibition of Malonyl CoA Decarboxylase Does Not Exacerbate Age-Related Insulin Resistance in Mice

Genetic and Pharmacological Inhibition of Malonyl CoA Decarboxylase Does Not Exacerbate Age-Related Insulin Resistance in Mice

Analyses of MbtB, MbtE, and MbtF Suggest Revisions to the Mycobactin Biosynthesis Pathway in Mycobacterium tuberculosis

In Vivo Characterization of Nonribosomal Peptide Synthetases NocA and NocB in the Biosynthesis of Nocardicin A

Contact Info

Product

Resources

About