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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Mechanistic Insights into Dideoxygenation in Gentamicin Biosynthesis

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Author(s):
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Li, Sicong [1] ; Bury, Priscila dos Santos [2] ; Huang, Fanglu [3] ; Guo, Junhong [1] ; Sun, Guo [1] ; Reva, Anna [3] ; Huang, Chuan [1] ; Jian, Xinyun [1] ; Li, Yuan [1] ; Zhou, Jiahai [4] ; Deng, Zixin [1] ; Leeper, Finian J. [5] ; Leadlay, Peter F. [3] ; Dias, Marcio V. B. [2, 6] ; Sun, Yuhui [1]
Total Authors: 15
Affiliation:
[1] Wuhan Univ, Key Lab Combinatorial Biosynth & Drug Discovery, Minist Educ, Wuhan 430071 - Peoples R China
[2] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, BR-05508000 Sao Paulo - Brazil
[3] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA - England
[4] Chinese Acad Sci, CAS Key Lab Quantitat Engn Biol, Shenzhen Inst Synthet Biol, Shenzhen Inst Adv Technol, Shenzhen 518055 - Peoples R China
[5] Univ Cambridge, Dept Chem, Cambridge CB2 1EW - England
[6] Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands - England
Total Affiliations: 6
Document type: Journal article
Source: ACS CATALYSIS; v. 11, n. 19, p. 12274-12283, OCT 1 2021.
Web of Science Citations: 0
Abstract

Gentamicin 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. (AU)

FAPESP's process: 14/07843-6 - Structural analysis of key enzymes for gentamicin and sisomicin biosynthesis
Grantee:Priscila dos Santos Bury
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 15/09188-8 - Biosynthesis of polyether and aminoglycoside antibiotics: structural investigation of unusual enzymes or with synthetic biology applicability
Grantee:Marcio Vinicius Bertacine Dias
Support Opportunities: Regular Research Grants
FAPESP's process: 10/15971-3 - Structural characterization of enzymes from antibiotic biosynthetic pathways with biotechnological interest
Grantee:Marcio Vinicius Bertacine Dias
Support Opportunities: Research Grants - Young Investigators Grants
FAPESP's process: 18/00351-1 - Applied structural biology involved in the biosynthesis of natural products: biotechnolgical aplications and study of unusual molecular reactions
Grantee:Marcio Vinicius Bertacine Dias
Support Opportunities: Regular Research Grants