Enzymes and Drugs

✍ Scribed by Kirkiacharian S., Dumond J.

• Publisher: ISTE Ltd and John Wiley & Sons
• Year: 2024
• Tongue: English
• Leaves: 216
• Category: Library

✦ Synopsis

Enzyme dysfunction, an essential catalyst for the smooth running of biochemical reactions and the maintenance of vital processes, is at the root of many pathologies that have paved the way for the development of numerous drugs.
Aimed at pharmacists, biologists, biochemists, doctors, veterinarians, medicinal chemists and students from a wide range of disciplines, Enzymes and Drugs brings together, for the first time, extensive documentation highlighting the relationships between a large number of drugs and enzymes. The book also highlights new prospects for therapeutic discoveries offered by enzyme targeting.
Numerous applications have been developed thanks to strategies for studying enzyme inhibition or activation, as well as the development of allosteric effectors, presented with their advantages and disadvantages. Various rare diseases, known as “orphan” diseases, have resulted from enzyme deficiency or absence. For their treatment, the introduction of substitute enzymes has led to major therapeutic advances.

✦ Table of Contents

Cover
Half Title
Enzymes and Drugs
Copyright
Contents
Preface
Introduction
1. Enzyme Kinetics, Inhibition and Activation
1.1. Michaelis and Menten theory
1.2. Irreversible inhibitors
1.3. Reversible inhibitors in a Michaelian system
1.3.1. Reversible competitive inhibitors
1.3.2. Reversible non-competitive inhibitors
1.3.3. Reversible uncompetitive inhibitors
1.4. Allostery: inhibitors and activators
1.4.1. Allosteric enzyme kinetics
1.4.1.1. K-type allosteric system
1.4.1.2. V-type allosteric system
1.4.2. Mechanism of allosteric enzyme regulation
1.4.2.1. Symmetrical model
1.4.2.2. Sequential model
1.5. References
2. Targeted Viral and Microbial Enzymes
2.1. Viral targets
2.1.1. Herpes group viruses: DNA-dependent DNA polymerases (EC 2)
2.1.2. Influenza virus: exo-alpha-sialidase or neuraminidase (EC 3)
2.1.3. HIV protease (EC 3)
2.1.4. HIV reverse transcriptase (RNA/DNA-dependent DNA polymerase – EC 2)
2.1.5. HIV integrase (EC 2)
2.1.6. Hepatitis C virus (HCV): RNA-dependent RNA polymerase (NS5B – EC 2) and viral protease (NS3-4A – EC 3)
2.2. Bacterial targets
2.2.1. Specific target (action mainly focused on the Mycobacterium tuberculosis species)
2.2.1.1. Alanine racemase (EC 5)
2.2.1.2. D-alanine-D-alanine ligase (EC 6)
2.2.1.3. Enoyl (Acyl-Carrier-Protein = ACP) reductase (EC 1)
2.2.1.4. Arabinosyltransferases (EC 2)
2.2.2. General actions
2.2.2.1. Targeting DNA-dependent RNA polymerase (EC 2)
2.2.2.2. Targeting DNA topoisomerase, gyrase (EC 5)
2.2.2.3. Targeting 30S or 50S ribosomal sub-units
2.2.2.3.1. Antibiotics acting on the 30S ribosomal sub-unit
2.2.2.3.2. Antibiotics acting on the 50S ribosomal sub-unit
2.2.2.4. Carboxypeptidases (EC 3), transpeptidases (EC 2), transglycosylases (EC 2), endopeptidases (EC 3) (Penicilline Binding Proteins – PBPs) and beta-lactamases (EC 3)
2.2.2.4.1. PBPs
2.2.2.4.2. Beta-lactamases
2.2.2.5. UDP-N-acetylglucosamine 1-carboxyvinyltransferase (EC 2)
2.2.2.6. Bacterial urease (EC 3)
2.2.2.7. Dihydrofolate synthetase (EC 6) and dihydrofolate reductase (EC 1)
2.2.2.8. Dihydropteroate synthase (EC 2)
2.3. Fungal targets
2.3.1. 1,3-beta-glucan synthase (EC 2)
2.3.2. Squalene mono-oxygenase (EC 1)
2.3.3. 14-sterol demethylase (EC 1)
2.3.4. Thymidylate synthase (EC 2)
2.4. Parasite targets
2.4.1. Ornithine decarboxylase (EC 4)
2.4.2. Heme polymerase (EC 2)
2.5. References
3. Targeted Human Enzymes
3.1. Treatment via effectors
3.1.1. Ophthalmology
3.1.1.1. Carbonic anhydrase (EC 4)
3.1.1.2. Aldose reductase (EC 1)
3.1.2. Neurology
3.1.2.1. Acetylcholinesterase (EC 3)
3.1.2.2. Monoamine oxidases A and B (EC 1)
3.1.2.3. L-amino aromatic acid decarboxylase (EC 4)
3.1.2.4. Catechol-O-methyltransferase (EC 2)
3.1.2.5. Succinate semi-aldehyde dehydrogenase (EC 1)
3.1.2.6. GABA transaminase (EC 2)
3.1.3. Metabolism and endocrinology
3.1.3.1. Hydroxyphenylpyruvate dioxygenase (EC 1)
3.1.3.2. Phenylalanine hydroxylase (EC 1)
3.1.3.3. Beta-hydroxysteroid dehydrogenase (EC 1)
3.1.3.4. Alcohol dehydrogenase (EC 1)
3.1.3.5. Aldehyde dehydrogenase (EC 1)
3.1.3.6. Dipeptidyl peptidase (several isoenzymes) (EC 3)
3.1.3.7. Alpha-glucosidases (EC 3)
3.1.3.8. ATPase H+/K+ (EC 3)
3.1.3.9. HMG-CoA reductase (EC 1)
3.1.3.10. Triacylglycerol lipases (pancreatic and gastric) (EC 3)
3.1.3.11. Xanthine oxidase (EC 1)
3.1.3.12. Enkephalinase (EC 3)
3.1.4. Cardiovascular and immunology
3.1.4.1. Phosphodiesterases (PDE–EC 3)
3.1.4.2. Cyclooxygenases (COX–EC 1)
3.1.4.2.1. Non-selective anti-inflammatories inhibiting COX-1 and COX-2
3.1.4.2.2. Selective COX-2 inhibitors
3.1.4.3. Histidine decarboxylase (EC 4)
3.1.4.4. Dihydroorotate dehydrogenase (EC 1)
3.1.4.5. Coagulation factor Xa (EC 3)
3.1.4.6. Inosine monophosphate dehydrogenase (EC 1)
3.1.4.7. Plasma kallikrein (EC 3)
3.1.4.8. Plasmin (EC 3)
3.1.4.9. Thrombin (EC 3)
3.1.4.10. Na+/K+ ATPase (EC 3)
3.1.4.11. Tyrosine 3-hydroxylase (EC 1)
3.1.4.12. Vitamin K (epoxy)-reductase (EC 1)
3.1.4.13. Angiotensin-converting enzyme (EC 3)
3.1.4.14. Renin (EC 3)
3.1.4.15. Nitric oxide synthases (EC 1)
3.1.5. Oncology
3.1.5.1. Adenosine deaminase (EC 3)
3.1.5.2. Dihydrofolate reductase (EC 1)
3.1.5.3. Thymidylate synthase (EC 2)
3.1.5.4. 3-Oxo-5-alpha steroid 4-dehydrogenase (EC 1)
3.1.5.5. DNA topoisomerase (EC 5)
3.1.5.6. Histone deacetylase (various isoenzymes) (EC 3)
3.1.5.7. Histone-lysine N-methyltransferase (EC 2)
3.1.5.8. Proteasome (EC 3)
3.1.5.9. Ribonucleoside diphosphate reductase (EC 1)
3.1.5.10. Cytochrome p450 (several isoforms, including aromatase) (EC 1)
3.1.5.11. Isocitrate dehydrogenases (EC 1)
3.1.5.12. DNA-dependent DNA polymerases (including telomerases) (EC 2)
3.1.5.13. Poly(ADP-ribose) polymerases (PARP) (EC 2)
3.1.6. Phosphatome and Kinome
3.1.6.1. Phosphatases (EC 3)
3.1.6.2. Kinases (EC 2)
3.1.6.2.1. Targeted kinases for anti-cancer treatments
3.1.6.2.2. Other non-cancer pathologies – JAK kinases
3.2. Enzyme replacement therapy
3.2.1. Gout
3.2.2. Acute leukemia and non-Hodgkin’s lymphoma
3.2.3. Hypophosphatasia
3.2.4. Chronic obstructive pulmonary disease
3.3. References
4. What are the New Targets?
4.1. Inhibition and activation strategies: advantages, disadvantages and current status
4.1.1. Irreversible inhibitors
4.1.1.1. Advantages
4.1.1.2. Disadvantages
4.1.2. Competitive inhibitors
4.1.2.1. Advantages
4.1.2.2. Disadvantages
4.1.3. Non-competitive inhibitors
4.1.3.1. Advantages
4.1.3.2. Disadvantages
4.1.4. Uncompetitive inhibitors
4.1.5. Allosteric effectors
4.1.5.1. Advantages
4.1.5.2. Disadvantages
4.1.6. Other strategies
4.2. Exogenous and endogenous targets
4.2.1. Exogenous targets
4.2.1.1. Coronavirus; SARS-CoV-2: RNA-dependent RNA polymerase (EC 2) and 3C like-protease (EC 3)
4.2.1.2. HIV protease (EC 3)
4.2.1.3. Integrase of the same virus
4.2.1.4. HIV reverse transcriptase (EC 2)
4.2.1.5. Respiratory syncytial virus (RSV)
4.2.1.6. Dihydrodipicolinate synthase (DHPDS) (EC 4)
4.2.1.7. GDP-mannose pyrophosphorylase (GDP-MP) (EC 2)
4.2.1.8. Fatty acid synthase (EC 2)
4.2.1.9. Isoleucine tRNA synthetase (EC 6)
4.2.2. Endogenous targets
4.2.2.1. Alpha-amylase (EC 3)
4.2.2.2. Enzymes involved in galactose metabolism
4.2.2.3. Enzymes involved in fructose metabolism
4.2.2.4. Arachidonate 5-lipoxygenase (EC 1)
4.2.2.5. Farnesyl-diphosphate farnesyltransferase (EC 2)
4.2.2.6. Histone acetyltransferase (various isoenzymes) (EC 2)
4.2.2.7. Phosphoribosylglycinamide formyltransferase (EC 2)
4.2.2.8. Thyroxine-5’-deiodinase (EC 1)
4.2.2.9. Carboxypeptidases (several isoforms for each type of carboxypeptidase) (EC 3)
4.2.2.10. Dioxygenases (EC 1)
4.2.2.11. Caspases (EC 3)
4.3. Rare diseases and enzymes
4.3.1. Lysosomal storage diseases
4.3.2. Other rare genetic diseases linked to one or more enzymes
4.4. References
5. Which “New” Drugs are We Moving Towards Now?
5.1. Chemistry
5.1.1. Combinatorial chemistry
5.1.2. Vectorization
5.2. Biology
5.2.1. Inducers and repressors
5.2.2. Antibodies
5.3. Genetics
5.3.1. Gene therapy
5.3.2. Antisense strategies
5.4. References
Conclusion
Index