PMID- 37751627
OWN - NLM
STAT- MEDLINE
DCOM- 20231011
LR  - 20231018
IS  - 1879-0909 (Electronic)
IS  - 0141-0229 (Linking)
VI  - 171
DP  - 2023 Dec
TI  - Production of an O-desmethylated product, a major human metabolite, of 
      rabeprazole sulfide by bacterial P450 enzymes.
PG  - 110328
LID - S0141-0229(23)00136-9 [pii]
LID - 10.1016/j.enzmictec.2023.110328 [doi]
AB  - Rabeprazole is a common type of proton pump inhibitor (PPI) used to treat various 
      peptic disorders. Unlike most PPI drugs, rabeprazole is spontaneously reduced to 
      rabeprazole sulfide (thioether) when it is given to patients. As a result, 
      rabeprazole sulfide is considered one of the active metabolites of rabeprazole. 
      Rabeprazole sulfide is mainly metabolized to desmethyl rabeprazole sulfide by 
      CYP2C19 and CYP2D6 in people. However, the pharmacological efficacy and safety of 
      desmethyl rabeprazole sulfide have not yet been investigated. Its usage is 
      challenging due to the high cost associated with the drug. In this study, we 
      found CYP102A1 mutants that can produce desmethyl rabeprazole sulfide as a major 
      metabolite of rabeprazole sulfide. The chemical characteristics of the major 
      product were confirmed using high-performance liquid chromatography, LC-mass 
      spectrometry, and nuclear magnetic resonance spectroscopy. CYP102A1 mutants 
      R47L/F87V/L188Q, R47L/F87V/L188Q/A335V/Q359R, and R47L/F87V/L188Q/I254V/D351E 
      showed k(cat) values of 39, 93, and 88 min(-1), respectively, for 
      O-desmethylation of rabeprazole sulfide. Furthermore, the highest concentration 
      of desmethyl rabeprazole sulfide product from 2 mM rabeprazole sulfide at optimal 
      conditions was obtained in bacterial whole-cell biotransformation with the 
      R47L/F87V/L188Q mutant, reaching 0.63 mM at 4-h incubation. In conclusion, we 
      present a platform that facilitates the efficient and sustainable production of 
      the desmethylated product from rabeprazole sulfide for use in the 
      biopharmaceutical industry.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Cao, Ngoc Tan
AU  - Cao NT
AD  - School of Biological Sciences and Technology, Chonnam National University, 77 
      Yongbongro, Gwangju 61186, Republic of Korea.
FAU - Cha, Gun Su
AU  - Cha GS
AD  - Namhae Garlic Research Institute, 2465-8 Namhaedaero, Gyeongsangnamdo 52430, 
      Republic of Korea.
FAU - Kim, Jeong-Hoon
AU  - Kim JH
AD  - School of Biological Sciences and Biotechnology, Graduate School, Chonnam 
      National University, 77 Yongbongro, Gwangju 61186, Republic of Korea.
FAU - Lee, Yujin
AU  - Lee Y
AD  - School of Biological Sciences and Biotechnology, Graduate School, Chonnam 
      National University, 77 Yongbongro, Gwangju 61186, Republic of Korea.
FAU - Yun, Chul-Ho
AU  - Yun CH
AD  - School of Biological Sciences and Technology, Chonnam National University, 77 
      Yongbongro, Gwangju 61186, Republic of Korea. Electronic address: 
      chyun@chonnam.ac.kr.
FAU - Nguyen, Ngoc Anh
AU  - Nguyen NA
AD  - School of Biological Sciences and Technology, Chonnam National University, 77 
      Yongbongro, Gwangju 61186, Republic of Korea. Electronic address: 
      nguyenanh@chonnam.ac.kr.
LA  - eng
PT  - Journal Article
DEP - 20230920
PL  - United States
TA  - Enzyme Microb Technol
JT  - Enzyme and microbial technology
JID - 8003761
RN  - 32828355LL (Rabeprazole)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - 0 (Proton Pump Inhibitors)
RN  - 0 (Sulfides)
SB  - IM
MH  - Humans
MH  - Rabeprazole
MH  - *Cytochrome P-450 Enzyme System/metabolism
MH  - *Proton Pump Inhibitors
MH  - Bacteria/metabolism
MH  - Sulfides
OTO - NOTNLM
OT  - CYP102A1 mutant
OT  - Cytochrome P450
OT  - O-desmethylation
OT  - Proton pump inhibitors
OT  - Rabeprazole sulfide
COIS- Declaration of Competing Interest The authors declare no conflict of interest.
EDAT- 2023/09/26 18:42
MHDA- 2023/10/11 06:45
CRDT- 2023/09/26 17:59
PHST- 2023/07/03 00:00 [received]
PHST- 2023/08/28 00:00 [revised]
PHST- 2023/09/18 00:00 [accepted]
PHST- 2023/10/11 06:45 [medline]
PHST- 2023/09/26 18:42 [pubmed]
PHST- 2023/09/26 17:59 [entrez]
AID - S0141-0229(23)00136-9 [pii]
AID - 10.1016/j.enzmictec.2023.110328 [doi]
PST - ppublish
SO  - Enzyme Microb Technol. 2023 Dec;171:110328. doi: 10.1016/j.enzmictec.2023.110328. 
      Epub 2023 Sep 20.