Abstract
Cytochrome P450 (CYP) bioreactors play a major role in establishing the practical use of this enzyme family in academia and industry. The current demand for enzymatic hydroxylations of unactivated carbons in the parmaceutical industry includes the preparation of drug metabolites and various hydroxylated synthetic precursors as well as the enzyme mediated lead diversification and natural product synthesis, most of which require multigram scale synthesis. To date, the large scale application of CYPs in the synthesis of oxygenated compounds is limited by many challenges. This review describes relevant examples of CYP oxidations and also presents the strategies available to overcome such challenges. At present, P450 catalyzed reactions can only be performed at substrate concentrations ranging from 1-25 mM, unlike other biocatalytic redox reactions like ketone reductases, typically performed at substrate loads greater than 500 mM. The emergence of powerful expression methods and a large number of CYP mutants developed for specific applications holds the promise for future industrial applications. The search for higher volumetric productivities is however a task that needs to be addressed not only through the use of protein engineering as the primary tool but significant emphasis needs to be placed on process development through exploring multiple operating schemes, optimizing reaction media and modifying microbial strains needed for heterologous expression.
Keywords: Bioreactor, CYP, challenges, oxidation, preparation, pharmaceutical, scale up.
Current Topics in Medicinal Chemistry
Title:Cytochrome P450 Bioreactors in the Pharmaceutical Industry: Challenges and Opportunities
Volume: 13 Issue: 12
Author(s): Carlos A. Martinez and Sanjeewa G. Rupasinghe
Affiliation:
Keywords: Bioreactor, CYP, challenges, oxidation, preparation, pharmaceutical, scale up.
Abstract: Cytochrome P450 (CYP) bioreactors play a major role in establishing the practical use of this enzyme family in academia and industry. The current demand for enzymatic hydroxylations of unactivated carbons in the parmaceutical industry includes the preparation of drug metabolites and various hydroxylated synthetic precursors as well as the enzyme mediated lead diversification and natural product synthesis, most of which require multigram scale synthesis. To date, the large scale application of CYPs in the synthesis of oxygenated compounds is limited by many challenges. This review describes relevant examples of CYP oxidations and also presents the strategies available to overcome such challenges. At present, P450 catalyzed reactions can only be performed at substrate concentrations ranging from 1-25 mM, unlike other biocatalytic redox reactions like ketone reductases, typically performed at substrate loads greater than 500 mM. The emergence of powerful expression methods and a large number of CYP mutants developed for specific applications holds the promise for future industrial applications. The search for higher volumetric productivities is however a task that needs to be addressed not only through the use of protein engineering as the primary tool but significant emphasis needs to be placed on process development through exploring multiple operating schemes, optimizing reaction media and modifying microbial strains needed for heterologous expression.
Export Options
About this article
Cite this article as:
Martinez A. Carlos and Rupasinghe G. Sanjeewa, Cytochrome P450 Bioreactors in the Pharmaceutical Industry: Challenges and Opportunities, Current Topics in Medicinal Chemistry 2013; 13 (12) . https://dx.doi.org/10.2174/15680266113139990111
DOI https://dx.doi.org/10.2174/15680266113139990111 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Oxidative Stress Modulation Through Habitual Physical Activity
Current Pharmaceutical Design Independent Relationship of Osteocalcin Circulating Levels with Obesity, Type 2 Diabetes, Hypertension, and HDL Cholesterol
Endocrine, Metabolic & Immune Disorders - Drug Targets The IL23/Th17 Pathway as a Therapeutic Target in Chronic Inflammatory Diseases
Inflammation & Allergy - Drug Targets (Discontinued) Hand Therapy Management of the Rheumatoid Wrist
Current Rheumatology Reviews The Salivary miRNome: A Promising Biomarker of Disease
MicroRNA Active Immunization Against Tumor Necrosis Factor-alpha Decreases Proinflammatory Cytokines, Oxidative Stress Mediators and Adhesion Molecules Risk Factors in Streptozotocin-induced Diabetic Rats
Endocrine, Metabolic & Immune Disorders - Drug Targets Novel Anticancer Targets and Drug Discovery in Post Genomic Age
Current Medicinal Chemistry - Anti-Cancer Agents In Vivo Anticancer Activity, Toxicology and Histopathological Studies of the Thiolate Gold(I) Complex [Au(Spyrimidine)(PTA-CH<sub>2</sub>Ph)]Br
Anti-Cancer Agents in Medicinal Chemistry Uric Acid and Diabetes: Is there a Link?
Current Pharmaceutical Design Synthesis of Novel Benzoquinones with Anti-Inflammatory Activity
Letters in Drug Design & Discovery Promoters and Control Elements: Designing Expression Cassettes for Gene Therapy
Current Gene Therapy Toll-Like Receptors: Role in Inflammation and Commensal Bacteria
Inflammation & Allergy - Drug Targets (Discontinued) Triazol-phenyl Antipyretic Derivatives Inhibit mPGES-1 mRNA Levels in LPS-Induced RAW 264.7 Macrophage Cells
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Drug Repurposing: An Emerging Tool for Drug Reuse, Recycling and Discovery
Current Drug Research Reviews Silymarin Extends Lifespan and Reduces Proteotoxicity in C. elegans Alzheimer’s Model
CNS & Neurological Disorders - Drug Targets Targeting Angiogenesis in Rheumatoid Arthritis
Current Rheumatology Reviews TNF-α Inhibition as a Treatment Strategy for Neurodegenerative Disorders: New Drug Candidates and Targets
Current Alzheimer Research Microglial Activation as a Compelling Target for Treating Acute Traumatic Brain Injury
Current Medicinal Chemistry Curcumin: A Dietary Phytochemical for Targeting the Phenotype and Function of Dendritic Cells
Current Medicinal Chemistry Proanthocyanidins in Health Care: Current and New Trends
Current Medicinal Chemistry