PMID- 23330869
OWN - NLM
STAT- MEDLINE
DCOM- 20130801
LR  - 20211021
IS  - 1520-5126 (Electronic)
IS  - 0002-7863 (Print)
IS  - 0002-7863 (Linking)
VI  - 135
IP  - 5
DP  - 2013 Feb 6
TI  - Non-ribosomal propeptide precursor in nocardicin A biosynthesis predicted from 
      adenylation domain specificity dependent on the MbtH family protein NocI.
PG  - 1749-59
LID - 10.1021/ja307710d [doi]
AB  - Nocardicin A is a monocyclic beta-lactam isolated from the actinomycete Nocardia 
      uniformis that shows moderate antibiotic activity against a broad spectrum of 
      gram-negative bacteria. The monobactams are of renewed interest due to emerging 
      gram-negative strains resistant to clinically available penicillins and 
      cephalosporins. Like isopenicillin N, nocardicin A has a tripeptide core of 
      non-ribosomal origin. Paradoxically, the nocardicin A gene cluster encodes two 
      non-ribosomal peptide synthetases (NRPSs), NocA and NocB, predicted to encode 
      five modules pointing to a pentapeptide precursor in nocardicin A biosynthesis, 
      unless module skipping or other nonlinear reactions are occurring. Previous 
      radiochemical incorporation experiments and bioinformatic analyses predict the 
      incorporation of p-hydroxy-L-phenylglycine (L-pHPG) into positions 1, 3, and 5 
      and L-serine into position 4. No prediction could be made for position 2. 
      Multidomain constructs of each module were heterologous expressed in Escherichia 
      coli for determination of the adenylation domain (A-domain) substrate specificity 
      using the ATP/PPi exchange assay. Three of the five A-domains, from modules 1, 2, 
      and 4, required the addition of stoichiometric amounts of MbtH family protein 
      NocI to detect exchange activity. On the basis of these analyses, the predicted 
      product of the NocA and NocB NRPSs is L-pHPG-L-Arg-D-pHPG-L-Ser-L-pHPG, a 
      pentapeptide. Despite being flanked by non-proteinogenic amino acids, proteolysis 
      of this pentapeptide by trypsin yields two fragments from cleavage at the C 
      terminus of the L-Arg residue. Thus, a proteolytic step is likely involved in the 
      biosynthesis of nocardicin A, a rare but precedented editing event in the 
      formation of non-ribosomal natural products that is supported by the 
      identification of trypsin-encoding genes in N. uniformis.
FAU - Davidsen, Jeanne M
AU  - Davidsen JM
AD  - Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, 
      United States.
FAU - Bartley, David M
AU  - Bartley DM
FAU - Townsend, Craig A
AU  - Townsend CA
LA  - eng
GR  - R01 AI014937/AI/NIAID NIH HHS/United States
GR  - R37 AI014937/AI/NIAID NIH HHS/United States
GR  - R56 AI014937/AI/NIAID NIH HHS/United States
GR  - AI014937/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130118
PL  - United States
TA  - J Am Chem Soc
JT  - Journal of the American Chemical Society
JID - 7503056
RN  - 0 (Lactams)
RN  - 0 (Oligopeptides)
RN  - 0 (Protein Precursors)
RN  - 76631-42-0 (nocardicin)
RN  - EC 6.3.2.- (Peptide Synthases)
RN  - EC 6.3.2.- (non-ribosomal peptide synthase)
SB  - IM
MH  - Lactams/chemistry/*metabolism
MH  - Molecular Structure
MH  - Nocardia/chemistry/metabolism
MH  - Oligopeptides/chemistry/*metabolism
MH  - Peptide Synthases/*metabolism
MH  - Polyadenylation
MH  - Protein Precursors/chemistry/*metabolism
PMC - PMC3571714
MID - NIHMS438177
EDAT- 2013/01/22 06:00
MHDA- 2013/08/02 06:00
PMCR- 2014/02/06
CRDT- 2013/01/22 06:00
PHST- 2013/01/22 06:00 [entrez]
PHST- 2013/01/22 06:00 [pubmed]
PHST- 2013/08/02 06:00 [medline]
PHST- 2014/02/06 00:00 [pmc-release]
AID - 10.1021/ja307710d [doi]
PST - ppublish
SO  - J Am Chem Soc. 2013 Feb 6;135(5):1749-59. doi: 10.1021/ja307710d. Epub 2013 Jan 
      18.