Article
Biochemistry & Molecular Biology
David C. Lamb, Jared Goldstone, Bin Zhao, Li Lei, Jonathan G. L. Mullins, Michael J. Allen, Steven L. Kelly, John J. Stegeman
Summary: Flavodoxins are small electron transport proteins involved in various metabolic pathways in bacteria, archaea, and algae. A bacteriophage called 0305 phi 8-36 was found to encode a flavodoxin protein, which has the potential to manipulate bacterial metabolism and affect the host biological fitness and microbiome. The flavodoxin was also shown to support specific chemical reactions in vitro and in vivo.
Article
Chemistry, Physical
F. Peter Guengerich, Stella A. Child, Ian R. Barckhausen, Margo H. Goldfarb
Summary: The bacterial cytochrome P450(cam) binds its substrate camphor through an induced-fit mechanism, where the enzyme changes conformation after binding the substrate. This behavior is different from other P450 enzymes that utilize a conformational selection process for substrate recognition. The accessory protein putidaredoxin has no effect on substrate binding, indicating a unique mechanism for substrate recognition by P450(cam).
Article
Chemistry, Multidisciplinary
Sebastian Adam, Dazhong Zheng, Andreas Klein, Carsten Volz, William Mullen, Sally L. Shirran, Brian O. Smith, Olga V. Kalinina, Rolf Mueller, Jesko Koehnke
Summary: In this study, we identified three proteins (CgnB, CgnC, and CgnE) responsible for the production of the tetracyclic crocagin core. Crystal structures of two homologues (CgnB and CgnE) provided insights into their functions. We also discovered the roles of CgnD and CgnL in the liberation and modification of the crocagin core, respectively, and proposed a biosynthetic scheme. Bioinformatic analyses further revealed potential pathways for the synthesis of structurally diverse peptide-derived pyrroloindoline alkaloids.
Article
Biochemistry & Molecular Biology
Christopher S. Campomizzi, George E. Ghanatios, D. Fernando Estrada
Summary: Cytochromes P450 are versatile enzymes involved in endogenous and exogenous metabolism, undergoing structural changes related to function. This study demonstrates the utility of fluorine (19F)-NMR spectroscopy in monitoring structural changes in CYP121A1, revealing insights into its role in substrate recognition and mechanistic details of this essential enzyme from Mycobacterium tuberculosis.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Dumei Ma, Libo Zhang, Yingwu Yin, Yuxing Gao, Qian Wang
Summary: This study investigated in detail the interactions between cycloalkyl phosphorus heterocycles and OleT(SA), revealing that hydrogen bonding and van der Waals forces play major roles in the interaction. The penetration of the cycloalkyl phosphorus heterocycles into the enzyme greatly affects the enzymatic activity of OleT(SA). This study provides an effective way to modulate the activity of cytochrome P450 enzymes using phosphorus heterocyclic compounds.
JOURNAL OF PHARMACEUTICAL ANALYSIS
(2021)
Review
Chemistry, Physical
Donya Valikhani, Juan M. Bolivar, Joelle N. Pelletier
Summary: Cytochrome P450s are a large superfamily of heme proteins with important applications in drug metabolism studies and biocatalytic transformations. Immobilization of P450 enzymes on biosensing platforms and in biocatalytic reactions plays a key role in improving operational stability. Various methods and materials have been developed to address the challenges associated with the unique characteristics of P450s in different applications.
Article
Multidisciplinary Sciences
Chunshun Li, Yifei Hu, Xiaohua Wu, Spencer D. Stumpf, Yunci Qi, John M. D'Alessandro, Keshav K. Nepal, Ariel M. Sarotti, Shugeng Cao, Joshua A. V. Blodgett
Summary: Rare actinomycetes are a valuable but underexploited source of bioactive compounds. In this study, a targeted metabologenomic approach was used to identify piperazyl compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. The discovery of two dimeric biaryl-cyclohexapeptides, petrichorins A and B, with potent anticancer activity, highlights the potential of rare actinomycetes for drug discovery.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Peter D. Giang, Luke R. Churchman, Jeanette E. Stok, Rochelle M. Soo, James J. De Voss
Summary: A study found that Rhodococcus globerulus (R. globerulus) isolated from soil beneath Eucalyptus sp. can thrive on mono-terpenes such as 1,8-cineole, p-cymene and (R)- and (S)-limonene as its sole sources of carbon and energy. The research revealed a novel cytochrome P450 (CYP108N12) in R. globerulus which may be responsible for initiating the biodegradation of structurally similar monoterpene compounds. This finding suggests that CYP108N12 has potential as a biocatalyst with specific hydroxylation capabilities.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2022)
Article
Biochemistry & Molecular Biology
Tianyi Yu, Marzhana Omarova, Meng Zhang, Istiak Hossain, Jianqiang Chen, Omead Darvish, Vijay T. John, Donghui Zhang
Summary: The cellular functions of membrane proteins are closely related to their structures and aggregation states. We have investigated the fragmentation of synthetic liposomes using hydrophobe-containing polypeptoids (HCPs). Our findings demonstrate that HCPs can effectively induce the fragmentation of liposomes into colloidally stable nanoscale HCP-lipid complexes, and have the potential for novel macromolecular surfactants for membrane protein extraction.
Article
Biochemistry & Molecular Biology
Arsenij Kokorin, Vlada B. Urlacher
Summary: In this study, fusion of P450 BM3 from Bacillus megaterium and an alcohol dehydrogenase from Sphingomonas yanoikuyae improved the two-step oxidation of (+)-valencene and resulted in increased production of (+)-nootkatone.
Review
Biotechnology & Applied Microbiology
Dani Permana, Takuya Kitaoka, Hirofumi Ichinose
Summary: Cytochrome P450s are heme-containing monooxygenases found in all biological kingdoms. Fungi, in particular, are an important source of diverse P450s that play key roles in sterol synthesis. This review discusses fungal P450s and their applications in bioconversion and biosynthesis, highlighting their history, availability, and versatility. The ability of P450s to catalyze various reactions makes them promising enzymes for numerous applications, and future research in this field is encouraged.
BIOTECHNOLOGY AND BIOENGINEERING
(2023)
Review
Chemistry, Inorganic & Nuclear
Lei Feng, Jing Ning, Xiangge Tian, Chao Wang, Zhenlong Yu, Xiaokui Huo, Tian Xie, Baojing Zhang, Tony D. James, Xiaochi Ma
Summary: Cytochrome P450 (CYP) enzymes are haem-containing proteins mainly involved in the oxidative metabolism of various chemicals. Fluorescent probes are useful molecular tools for selectively detecting CYP activity, facilitating important insights into the activity expression of CYP enzymes.
COORDINATION CHEMISTRY REVIEWS
(2021)
Article
Biochemistry & Molecular Biology
Ting Xiong, Si-quan Ling, Jia-li Liu, Xin-nian Zeng
Summary: This article studied the toxicity of Fluralaner against S. invicta and the involvement of metabolism-related enzymes in the metabolism process of Fluralaner. The results showed that Fluralaner was effective against S. invicta through topical application and feeding application, and cytochrome P450 monooxygenase and carboxylesterase might be involved in the detoxification of Fluralaner.
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Jeffrey Yin, Lucas Hill, Marlina Mansour, Summer Collier, Pranab Barman
Summary: Co-administration of HCV DAAs with anti-epileptics or mood stabilizers with inducing properties is contraindicated. However, using CYP and drug transport inhibitors as pharmacokinetic enhancers can potentially overcome induction effects and achieve SVR. This strategy was successful in three patients without safety concerns.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2023)
Article
Biotechnology & Applied Microbiology
Ru-Yi Ye, Juan Song, Zhi-Jun Zhang, Hui-Lei Yu
Summary: CYP120As are unique non-membrane P450 enzymes that play a significant role in the biodegradation of retinoids, with promising catalytic potential.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2023)
Article
Spectroscopy
Yilin Liu, Kirsty J. McLean, Andrew W. Munro, James R. Kincaid
JOURNAL OF RAMAN SPECTROSCOPY
(2018)
Article
Biochemistry & Molecular Biology
Hend A. A. Abd El-Wahab, Mauro Accietto, Leonardo B. Marino, Kirsty J. McLean, Colin W. Levy, Hamdy M. Abdel-Rahman, Mahmoud A. El-Gendy, Andrew W. Munro, Ahmed S. Aboraia, Claire Simons
BIOORGANIC & MEDICINAL CHEMISTRY
(2018)
Article
Biochemistry & Molecular Biology
Safaa M. Kishk, Kirsty J. McLean, Sakshi Sood, Mohamed A. Helal, Mohamed S. Gomaa, Ismail Salama, Samia M. Mostafa, Luiz Pedro S. de Carvalho, Andrew W. Munro, Claire Simons
BIOORGANIC & MEDICINAL CHEMISTRY
(2019)
Article
Multidisciplinary Sciences
Laura N. Jeffreys, Harshwardhan Poddar, Marina Golovanova, Colin W. Levy, Hazel M. Girvan, Kirsty J. McLean, Michael W. Voice, David Leys, Andrew W. Munro
SCIENTIFIC REPORTS
(2019)
Article
Chemistry, Multidisciplinary
Safaa M. Kishk, Kirsty J. McLean, Sakshi Sood, Darren Smith, Jack W. D. Evans, Mohamed A. Helal, Mohamed S. Gomaa, Ismail Salama, Samia M. Mostafa, Luiz Pedro S. de Carvalho, Colin W. Levy, Andrew W. Munro, Claire Simons
Article
Chemistry, Medicinal
Sarah Matthews, Kamila J. Pacholarz, Aidan P. France, Thomas A. Jowitt, Sam Hay, Perdita Barran, Andrew W. Munro
ACS INFECTIOUS DISEASES
(2019)
Article
Chemistry, Medicinal
Sunnia Rajput, Kirsty J. McLean, Harshwardhan Poddar, Irwin R. Selvam, Gayathri Nagalingam, James A. Triccas, Colin W. Levy, Andrew W. Munro, Craig A. Hutton
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Martyn Frederickson, Irwin R. Selvam, Dimitrios Evangelopoulos, Kirsty J. McLean, Mona M. Katariya, Richard B. Tunnicliffe, Bethany Campbell, Madeline E. Kavanagh, Sitthivut Charoensutthivarakul, Richard T. Blankley, Colin W. Levy, Luiz Pedro S. de Carvalho, David Leys, Andrew W. Munro, Anthony G. Coyne, Chris Abell
Summary: A novel strategy combining X-ray crystallographic screening with phenotypic screening is described for hit generation against promising tuberculosis (TB) targets. This method provides validation of target engagement and determination of in vitro activity. The utility of this approach is demonstrated through the screening against CYP121A1, a validated drug discovery target for TB. Several compounds showed promising activity against Mycobacterium tuberculosis strain H37Rv, and structure-based design resulted in analogues with pan-assay activity. This study highlights the importance of developing new drugs for combating drug resistance in TB.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Sian Thistlethwaite, Laura N. Jeffreys, Hazel M. Girvan, Kirsty J. McLean, Andrew W. Munro
Summary: BM3 is a catalytically self-sufficient flavocytochrome fusion protein that can be engineered to produce a variety of drug-like compounds. Through modification of key residues within the BM3 active site, its catalytic repertoire can be expanded to generate diverse metabolites.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Physical
Mark A. Ashworth, Elvira Bombino, Rene M. de Jong, Hein J. Wijma, Dick B. Janssen, Kirsty J. McLean, Andrew W. Munro
Summary: In this study, further optimization of the stereoselectivity of CYP105AS1 was achieved using computationally aided approach. A small set of eight mutants with desired selectivity were designed and tested experimentally, with the best variant showing >99% stereoselective hydroxylation of compactin to pravastatin. Molecular dynamics simulations supported the experimentally observed stereoselectivity.
Article
Chemistry, Multidisciplinary
Mona M. Katariya, Matthew Snee, Richard B. Tunnicliffe, Madeline E. Kavanagh, Helena I. M. Boshoff, Cecilia N. Amadi, Colin W. Levy, Andrew W. Munro, Chris Abell, David Leys, Anthony G. Coyne, Kirsty J. McLean
Summary: Mycobacterium tuberculosis (Mtb) caused approximately 1.6 million deaths in 2021. Due to the emergence of drug resistance, there is an urgent need for new therapeutic agents and ongoing drug discovery efforts. Host-derived lipids like cholesterol not only support Mtb growth but also play a role in immunomodulation and immune evasion. Mtb cytochrome P450 (CYP) enzymes, particularly CYP125 and CYP142, are potential targets for inhibition in lipid catabolism. Compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore showed strong binding to both CYP125 and CYP142, with in-cell activity against drug-resistant isolates. These findings are important for developing additional treatment options and exploring the role of CYP125 and CYP142 in Mtb pathogenesis.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)