The proposed studies on enzymatic reaction mechanism will lead to the characterization of enzymes in microbial and parasite metabolism that may be candidate targets for new drug developments themselves or produce new pharmacology. The study of the four E. coli genes Mcb A,B,C,D that convert the 43 amino acid polypeptide microcin A into the highly potent antibiotic microcin B17 that inhibits DNA gyrase will reveal the molecular enzymology of oxazole and thiazole biogenesis from gly-ser and gly-cys dipeptide sequences and of oxazole-thiazole and thiazole-oxazole bisheterocycles from gly-ser-cys and gly-cys-ser sequences in the same 43aa precursor. These bis heterocycles are probably DNA intercalators and the mechanism of enzymic formation has been obscure to date. Characterization of the E. coli acyl carrier protein synthase (ACPS) will provide molecular understanding of protein recognition of this posttranslational conversion of specific serine residues into P- pantetheinyl groups that serve as obligate prosthetic groups in macrolide, depsipeptide, and nonribosomal peptide antibiotic biogenesis. The third project, analysis of the bifunctional glutathionylspermidine (Gsp) synthetase/amidase of E. coli and congeneric Gsp synthase and bis- Gsp (trypanothione) synthase in kinetoplastid parasites, will reveal molecular strategy for formation of this unusual pair of glutathionyl polyamine metabolites in these parasitic protozoa, a pathway that should sensitize trypanosomatids to oxidant stress.

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National Institute of General Medical Sciences (NIGMS)
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Biochemistry Study Section (BIO)
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Harvard University
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Tsodikov, Oleg V; Hou, Caixia; Walsh, Christopher T et al. (2015) Crystal structure of O-methyltransferase CalO6 from the calicheamicin biosynthetic pathway: a case of challenging structure determination at low resolution. BMC Struct Biol 15:13
Walsh, Christopher T; Wencewicz, Timothy A (2014) Prospects for new antibiotics: a molecule-centered perspective. J Antibiot (Tokyo) 67:7-22
Setser, Jeremy W; Heemstra Jr, John R; Walsh, Christopher T et al. (2014) Crystallographic evidence of drastic conformational changes in the active site of a flavin-dependent N-hydroxylase. Biochemistry 53:6063-77
Walsh, Christopher T; Haynes, Stuart W; Ames, Brian D et al. (2013) Short pathways to complexity generation: fungal peptidyl alkaloid multicyclic scaffolds from anthranilate building blocks. ACS Chem Biol 8:1366-82
Haynes, Stuart W; Gao, Xue; Tang, Yi et al. (2013) Complexity generation in fungal peptidyl alkaloid biosynthesis: a two-enzyme pathway to the hexacyclic MDR export pump inhibitor ardeemin. ACS Chem Biol 8:741-8
Gao, Xue; Jiang, Wei; Jiménez-Osés, Gonzalo et al. (2013) An iterative, bimodular nonribosomal peptide synthetase that converts anthranilate and tryptophan into tetracyclic asperlicins. Chem Biol 20:870-8
Walsh, Christopher T; O'Brien, Robert V; Khosla, Chaitan (2013) Nonproteinogenic amino acid building blocks for nonribosomal peptide and hybrid polyketide scaffolds. Angew Chem Int Ed Engl 52:7098-124
Parker, Jared B; Walsh, Christopher T (2013) Action and timing of BacC and BacD in the late stages of biosynthesis of the dipeptide antibiotic bacilysin. Biochemistry 52:889-901
Malcolmson, Steven J; Young, Travis S; Ruby, J Graham et al. (2013) The posttranslational modification cascade to the thiopeptide berninamycin generates linear forms and altered macrocyclic scaffolds. Proc Natl Acad Sci U S A 110:8483-8
Walsh, Christopher T; Wencewicz, Timothy A (2013) Flavoenzymes: versatile catalysts in biosynthetic pathways. Nat Prod Rep 30:175-200

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