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Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics.

Publication ,  Journal Article
Zhang, W; Ntai, I; Bolla, ML; Malcolmson, SJ; Kahne, D; Kelleher, NL; Walsh, CT
Published in: Journal of the American Chemical Society
April 2011

Pacidamycins are a family of uridyl peptide antibiotics that inhibit the translocase MraY, an essential enzyme in bacterial cell wall biosynthesis that to date has not been clinically targeted. The pacidamycin structural skeleton contains a doubly inverted peptidyl chain with a β-peptide and a ureido linkage as well as a 3'-deoxyuridine nucleoside attached to DABA(3) of the peptidyl chain via an enamide linkage. Although the biosynthetic gene cluster for pacidamycins was identified recently, the assembly line of this group of peptidyl nucleoside antibiotics remained poorly understood because of the highly dissociated nature of the encoded nonribosomal peptide synthetase (NRPS) domains and modules. This work has identified a minimum set of enzymes needed for generation of the pacidamycin scaffold from amino acid and nucleoside monomers, highlighting a freestanding thiolation (T) domain (PacH) as a key carrier component in the peptidyl chain assembly as well as a freestanding condensation (C) domain (PacI) catalyzing the release of the assembled peptide by a nucleoside moiety. On the basis of the substrate promiscuity of this enzymatic assembly line, several pacidamycin analogues were produced using in vitro total biosynthesis.

Duke Scholars

Published In

Journal of the American Chemical Society

DOI

EISSN

1520-5126

ISSN

0002-7863

Publication Date

April 2011

Volume

133

Issue

14

Start / End Page

5240 / 5243

Related Subject Headings

  • Streptomyces
  • Pyrimidine Nucleosides
  • Peptides
  • General Chemistry
  • Enzymes
  • Bacterial Proteins
  • Anti-Bacterial Agents
  • 40 Engineering
  • 34 Chemical sciences
  • 03 Chemical Sciences
 

Citation

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Zhang, W., Ntai, I., Bolla, M. L., Malcolmson, S. J., Kahne, D., Kelleher, N. L., & Walsh, C. T. (2011). Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics. Journal of the American Chemical Society, 133(14), 5240–5243. https://doi.org/10.1021/ja2011109
Zhang, Wenjun, Ioanna Ntai, Megan L. Bolla, Steven J. Malcolmson, Daniel Kahne, Neil L. Kelleher, and Christopher T. Walsh. “Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics.Journal of the American Chemical Society 133, no. 14 (April 2011): 5240–43. https://doi.org/10.1021/ja2011109.
Zhang W, Ntai I, Bolla ML, Malcolmson SJ, Kahne D, Kelleher NL, et al. Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics. Journal of the American Chemical Society. 2011 Apr;133(14):5240–3.
Zhang, Wenjun, et al. “Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics.Journal of the American Chemical Society, vol. 133, no. 14, Apr. 2011, pp. 5240–43. Epmc, doi:10.1021/ja2011109.
Zhang W, Ntai I, Bolla ML, Malcolmson SJ, Kahne D, Kelleher NL, Walsh CT. Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics. Journal of the American Chemical Society. 2011 Apr;133(14):5240–5243.
Journal cover image

Published In

Journal of the American Chemical Society

DOI

EISSN

1520-5126

ISSN

0002-7863

Publication Date

April 2011

Volume

133

Issue

14

Start / End Page

5240 / 5243

Related Subject Headings

  • Streptomyces
  • Pyrimidine Nucleosides
  • Peptides
  • General Chemistry
  • Enzymes
  • Bacterial Proteins
  • Anti-Bacterial Agents
  • 40 Engineering
  • 34 Chemical sciences
  • 03 Chemical Sciences