Journal
SCIENCE ADVANCES
Volume 7, Issue 34, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abh0250
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Funding
- Deutsche Akademie fur Naturforscher Leopoldina, Germany
- Wellcome Trust [210734/Z/18/Z, 106244/Z/14/Z]
- Biotechnology and Biological Sciences Research Council [BB/M011224/1]
- Royal Society Wolfson Fellowship [RSWF\R2\182017]
- Ineos Oxford Institute
- Cancer Research UK
- EPSRC Synthesis for Biology and Medicine CDT [EP/L015838/1]
- Clarendon Scholarship
- St. John's College, Oxford
- Medical Research Foundation [MRF-145-0004-TPG-AVISO]
- NIH [GM133081, 1P41GM139687, GM117126, GM55302, GM110501, GM126289, S10 OD023453]
- Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences (BES), Division of Chemical Sciences, Geosciences, and Biosciences
- U.S. DOE, Office of Science, BES [DE-AC02-76SF00515]
- DOE, Office of Science [DE-AC02-05CH11231]
- Medical Research Foundation [MRF-145-0004-TPG-AVISO] Funding Source: researchfish
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IPNS catalyzes the reaction between ACV and dioxygen to produce IPN, revealing the importance of protein dynamics in regulating intermediate conformations. This study also has implications for catalysis by multiple IPNS-related oxygenases.
Isopenicillin N synthase (IPNS) catalyzes the unique reaction of L-delta-(alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV) with dioxygen giving isopenicillin N (IPN), the precursor of all natural penicillins and cephalosporins. X-ray free-electron laser studies including time-resolved crystallography and emission spectroscopy reveal how reaction of IPNS:Fe(II):ACV with dioxygen to yield an Fe(III) superoxide causes differences in active site volume and unexpected conformational changes that propagate to structurally remote regions. Combined with solution studies, the results reveal the importance of protein dynamics in regulating intermediate conformations during conversion of ACV to IPN. The results have implications for catalysis by multiple IPNS-related oxygenases, including those involved in the human hypoxic response, and highlight the power of serial femtosecond crystallography to provide insight into long-range enzyme dynamics during reactions presently impossible for nonprotein catalysts.
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