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
-
Reliability of Virtual Screening Methods in Prediction of PDE4Binhibitor Activity
Current Drug Discovery Technologies Adverse Cardiovascular Effects of Antirheumatic Drugs: Implications for Clinical Practice and Research
Current Pharmaceutical Design Small Molecule p38 MAP Kinase Inhibitors for the Treatment of Inflammatory Diseases: Novel Structures and Developments During 2006- 2008
Current Topics in Medicinal Chemistry Protein Regulators of Eicosanoid Synthesis: Role in Inflammation
Current Protein & Peptide Science The Multiple Roles of The Transcription Factors MAZ and Pur-1, Two Proteins encoded by Housekeeping Genes
Current Genomics Three Levels Face Centered Central Composite Design of Colon Targeted Micro-Particulates System of Celecoxib: Screening of Formulations Variables and in vivo Studies
Current Drug Delivery Cachexia and Herbal Medicine: Perspective
Current Pharmaceutical Design The Emerging Diabetes Online Community
Current Diabetes Reviews Psoriatic Arthritis – Review of the Immunologic, Clinic and Therapeutic Aspects of an Inflammatory Systemic Disease
Current Rheumatology Reviews Human Chorionic Gonadotropin: A Model Molecule For Oligopeptide-Based Drug Discovery
Endocrine, Metabolic & Immune Disorders - Drug Targets Interleukin 20
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Pharmacogenetics in Treatment of Rheumatoid Arthritis
Current Pharmaceutical Design Stem Cell Therapies for Intervertebral Disc Degeneration: Immune Privilege Reinforcement by Fas/FasL Regulating Machinery
Current Stem Cell Research & Therapy Xanthine Oxidase and its Role as Target in Cardiovascular Disease: Cardiovascular Protection by Enzyme Inhibition?
Current Pharmaceutical Design Survey of Epstein Barr Virus (EBV) Immunogenic Proteins and their Epitopes: Implications for Vaccine Preparation
Recent Patents on Anti-Infective Drug Discovery In vivo, Extract from Withania somnifera Root Ameliorates Arthritis via Regulation of Key Immune Mediators of Inflammation in Experimental Model of Arthritis
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Medication Adherence of Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis Considering the Psychosocial Factors, Health Literacy and Current Life Concerns of Patients
Current Rheumatology Reviews Formulation and Characterizations of Delayed Release Multi-Particulates System of Indomethacin: Optimization by Response Surface Methodology
Current Drug Delivery Dysregulation of SIRT-1 Signaling in Multiple Sclerosis and Neuroimmune Disorders: A Systematic Review of SIRTUIN Activators as Potential Immunomodulators and their Influences on other Dysfunctions
Endocrine, Metabolic & Immune Disorders - Drug Targets Natural Anticoagulant Proteins in the Regulation of Autoimmunity: Potential Role of Protein S
Current Pharmaceutical Design