uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The mechanism for isopenicillin N synthase from density-functional modeling highlights the similarities with other enzymes in the 2-his-1-carboxylate family
Kyoto Univ, Fukui Inst Fundamental Chem, Sakyo Ku, Kyoto 6068103, Japan.ORCID iD: 0000-0002-1312-1202
Stockholm Univ, Dept Phys, Quantum Chem Grp, SE-10691 Stockholm, Sweden.
Kyoto Univ, Fukui Inst Fundamental Chem, Sakyo Ku, Kyoto 6068103, Japan.
2008 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 47, no 3, 1031-1042 p.Article in journal (Refereed) Published
Abstract [en]

Isopenicillin N synthase (IPNS) catalyzes a key step in the biosynthesis of the important P-lactam antibiotics penicillins and cephalosporins. Density-functional calculations with the B3LYP functional are used to propose a detailed mechanism for this reaction. The results support the general scheme outlined from experimental observations, with formation of a four-membered beta-lactam ring followed by formation of a five-membered thiazolidine ring. However, an alternative mechanism for the heterolytic O-O bond cleavage and beta-lactam ring formation steps is proposed. The former part involves protonation of the distal oxygen by an iron-bound water ligand. This mechanism highlights the strong similarities that exist between IPNS and other enzymes of the 2-histidine-1-carboxylate family, especially pterin-dependent amino acid hydroxylases and alpha-keto acid-dependent dioxygenases. Both activation of the cysteine beta-C-H bond by an iron-bound superoxo radical and activation of the valine beta-C-H bond by a ferryl-oxo species show reaction barriers close to the experimentally measured one. These results are in agreement with kinetic isotope experiments that suggest both C-H bond activation steps to be partially rate limiting. The ring formation sequence is determined by the relative strengths of the two C-H bonds. Only the ferryl-oxo intermediate is capable of activating the stronger valine beta-C-H bond.

Place, publisher, year, edition, pages
2008. Vol. 47, no 3, 1031-1042 p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-145473DOI: 10.1021/bi701577qISI: 000252415500018PubMedID: 18163649OAI: oai:DiVA.org:uu-145473DiVA: diva2:396502
Available from: 2011-02-10 Created: 2011-02-09 Last updated: 2017-12-11Bibliographically approved

Open Access in DiVA

fulltext(4690 kB)120 downloads
File information
File name FULLTEXT01.pdfFile size 4690 kBChecksum SHA-512
5acfef6c3e2146e91cb635489b53c6e371f7bfb18c6f5c07f6b0ba02ecbe74eb67bbb5a4f312b85d55ca2af454fdfcc3bdf5e84551424c9425033483570f84c7
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Lundberg, Marcus

Search in DiVA

By author/editor
Lundberg, Marcus
In the same journal
Biochemistry
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 120 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 751 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf