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Mechanistic Insights into Dideoxygenation in Gentamicin Biosynthesis

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cam.issuedOnline2021-09-20
dc.contributor.authorLi, S
dc.contributor.authorSantos Bury, PD
dc.contributor.authorHuang, F
dc.contributor.authorGuo, J
dc.contributor.authorSun, G
dc.contributor.authorReva, A
dc.contributor.authorHuang, C
dc.contributor.authorJian, X
dc.contributor.authorLi, Y
dc.contributor.authorZhou, J
dc.contributor.authorDeng, Z
dc.contributor.authorLeeper, FJ
dc.contributor.authorLeadlay, PF
dc.contributor.authorDias, MVB
dc.contributor.authorSun, Y
dc.contributor.orcidHuang, F [0000-0002-0320-299X]
dc.contributor.orcidDias, MVB [0000-0002-5312-0191]
dc.contributor.orcidSun, Y [0000-0001-5720-9620]
dc.date.accessioned2021-11-06T00:31:45Z
dc.date.available2021-11-06T00:31:45Z
dc.date.issued2021
dc.description.abstractGentamicin is an important aminoglycoside antibiotic used for treatment of infections caused by Gram-negative bacteria. Although most of the biosynthetic pathways of gentamicin have been elucidated, a remaining intriguing question is how the intermediates JI-20A and JI-20B undergo a dideoxygenation to form gentamicin C complex. Here we show that the dideoxygenation process starts with GenP-catalyzed phosphorylation of JI-20A and JI-20Ba. The phosphorylated products are successively modified by concerted actions of two PLP (pyridoxal 5′-phosphate)-dependent enzymes: elimination of water and then phosphate by GenB3 and double bond migration by GenB4. Each of these reactions liberates an imine which hydrolyses to a ketone or aldehyde and is then reaminated by GenB3 using an amino donor. Importantly, crystal structures of GenB3 and GenB4 have guided site-directed mutagenesis to reveal crucial residues for the enzymes’ functions. We propose catalytic mechanisms for GenB3 and GenB4, which shed light on the already unrivalled catalytic versatility of PLP-dependent enzymes.
dc.identifier.doi10.17863/CAM.77826
dc.identifier.eissn2155-5435
dc.identifier.issn2155-5435
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330383
dc.language.isoeng
dc.publisherAmerican Chemical Society (ACS)
dc.publisher.urlhttp://dx.doi.org/10.1021/acscatal.1c03508
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectaminoglycoside biosynthesis
dc.subjectantibiotic
dc.subjectdeoxygenation
dc.subjectPLP-dependent enzyme
dc.subjectcrystal structure
dc.titleMechanistic Insights into Dideoxygenation in Gentamicin Biosynthesis
dc.typeArticle
dcterms.dateAccepted2021-08-30
prism.endingPage12283
prism.issueIdentifier19
prism.publicationDate2021
prism.publicationNameACS Catalysis
prism.startingPage12274
prism.volume11
pubs.funder-project-idMedical Research Council (G1001687)
pubs.funder-project-idMedical Research Council (MR/M019020/1)
rioxxterms.licenseref.startdate2021-10-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1021/acscatal.1c03508

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