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Structure and mechanism of piperideine-6-carboxylate dehydrogenase from Streptomyces clavuligerus
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.ORCID iD: 0000-0001-8710-327x
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.ORCID iD: 0000-0002-7565-0177
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
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2019 (English)In: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, ISSN 2059-7983, Vol. 75, p. 1107-1118Article in journal (Refereed) Published
Abstract [en]

The core of beta-lactam antibiotics originates from amino acids of primary metabolism in certain microorganisms. beta-Lactam-producing bacteria, including Streptomyces clavuligerus, synthesize the precursor of the amino acid alpha-aminoadipic acid by the catabolism of lysine in two steps. The second reaction, the oxidation of piperideine-6-carboxylate (or its open-chain form alpha-aminoadipate semialdehyde) to alpha-aminoadipic acid, is catalysed by the NAD(+)-dependent enzyme piperideine-6-carboxylate dehydrogenase (P6CDH). This structural study, focused on ligand binding and catalysis, presents structures of P6CDH from S. clavuligerus in its apo form and in complexes with the cofactor NAD(+), the product alpha-aminoadipic acid and a substrate analogue, picolinic acid. P6CDH adopts the common aldehyde dehydrogenase fold, consisting of NAD-binding, catalytic and oligomerization domains. The product binds in the oxyanion hole, close to the catalytic residue Cys299. Clear density is observed for the entire cofactor, including the nicotinamide riboside, in the binary complex. NAD(+) binds in an extended conformation with its nicotinamide ring overlapping with the binding site of the carboxylate group of the product, implying that the conformation of the cofactor may change during catalysis. The binding site of the substrate analogue overlaps with that of the product, suggesting that the cyclic form of the substrate, piperideine-6-carboxylate, may be accepted as a substrate by the enzyme. The catalytic mechanism and the roles of individual residues are discussed in light of these results.

Place, publisher, year, edition, pages
INT UNION CRYSTALLOGRAPHY , 2019. Vol. 75, p. 1107-1118
Keywords [en]
beta-lactam biosynthesis pathway, alpha-aminoadipic acid, beta-lactam antibiotics, picolinic acid, Streptomyces clavuligerus, aldehyde dehydrogenase fold, enzyme mechanism
National Category
Structural Biology Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-400425DOI: 10.1107/S2059798319014852ISI: 000501134600007PubMedID: 31793904OAI: oai:DiVA.org:uu-400425DiVA, id: diva2:1381278
Available from: 2019-12-20 Created: 2019-12-20 Last updated: 2019-12-20Bibliographically approved

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Hasse, DirkCarlsson, GunillaAndersson, Inger

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