Metalloenzymes

Metalloenzymes: From Bench to Bedside offers a thorough overview of metalloenzymes, spanning biochemical and structural features, pharmacology, and biotechnological applications. After a brief overview, international experts in the field discuss a wide range of magnesium, calcium, zinc, manganese, nickel, iron, copper, cadmium, molybdenum, and tungsten enzymes, along with catalytic roles within their active sites. With a uniform approach throughout, each chapter includes the structure and function of the enzyme, physiologic and pathologic roles, inhibitors and activators of the enzyme (and their design), and clinical agents or compounds applied in medicine and drug discovery. This book enables scientists across academia and industry to adopt ongoing metalloenzyme research, and continuous discovery of novel metalloenzymes, in new life science studies and clinical applications.

Cover image
Title page
Table of Contents
Copyright
Contributors
Preface
Section A: Metalloenzymes
Chapter 1: Introduction to metalloenzymes: From bench to bedside
Abstract
1: Introduction
2: Druggability of metalloenzymes: Challenges and opportunities
References
Section B: Magnesium and calcium-containing enzymes
Chapter 2.1: DNA and RNA polymerases
Abstract
1: Structure and function of the enzyme(s)
2: Physiologic/pathologic role
3: Classes of inhibitors/activators and their design
4: Polymerase inhibitors in clinical use or in advanced development stages
References
Chapter 2.2: Reverse transcriptase
Abstract
1: An overview of reverse transcriptase function
2: Structure and function of HIV-1 reverse transcriptase
3: Structure and function of Ty3 retrotransposon
4: Structure and function of telomerase reverse transcriptase
5: Clinically used inhibitors
References
Chapter 2.3: Integrase
Abstract
1: Introduction
2: Structure of IN
3: Reactions catalyzed by the IN enzyme
4: IN-strand transfer inhibitors (INSTIs)
5: First-generation INSTIs
6: Second-generation INSTIs
7: New perspectives for IN inhibition
8: Dual-acting inhibitors
9: Conclusion
References
Chapter 2.4: Cyclin-dependent kinase 2 (CDK2)
Abstract
1: Structure and function of CDK2
2: Physiologic and pathologic role of CDK2
3: Classes of inhibitors and their design
4: Clinically used agents or compounds in clinical development
References
Chapter 2.5: Catechol-O-methyltransferase (COMT)
Abstract
1: Structure and function of the catechol-O-methyltransferase (COMT) enzyme
2: Physiologic and pathologic roles of COMT
3: Inhibitors of COMT and their design
4: Clinically used agents or compounds in clinical development
5: Conclusions
References
Chapter 2.6: d-Alanine-d-alanine ligase
Abstract
1: Introduction
2: Structure and function of Ddl
3: Ddl inhibitors
4: Conclusions
References
Chapter 2.7: Paraoxonases
Abstract
1: Introduction
2: Structure and functions of CAs
3: Catalyzed reactions
4: PON inhibition
5: Physiological/pathological roles of PONs
6: Conclusions
References
Chapter 2.8: Phospholipases A2
Abstract
Acknowledgments
1: Structure and function of the PLA2 superfamily of enzymes
2: Physiologic and pathologic roles of PLA2 enzymes
3: Classes of PLA2 inhibitors and their design
4: Conclusions
References
Section C: Zinc enzymes
Chapter 3.1: Carbonic anhydrases
Abstract
1: Introduction
2: Catalyzed reactions, structure and functions of CAs
3: CA inhibition mechanisms, classes of inhibitors
4: CA inhibitors in clinical use
5: CA activators
6: Conclusions and future prospects
References
Chapter 3.2: Metallo-β-lactamases
Abstract
Acknowledgments
1: Introduction
2: Structure and function of metallo-β-lactamases
3: Physiologic and pathologic role of metallo-β-lactamases
4: Classes of metallo-β-lactamase inhibitors and their design
5: Metallo-β-lactamase inhibitors in clinical development
6: Conclusion
References
Chapter 3.3: Bacterial zinc proteases
Abstract
1: Introduction
2: Bacterial metalloproteases
3: Bacterial collagenase
4: Pseudolysin
5: The neurotoxins produced by tetanus and botulinum
6: Anthrax toxin lethal factor
7: Conclusions
References
Chapter 3.4: Matrix metalloproteases
Abstract
1: Structure and function of the enzyme(s)
2: Physiologic/pathologic role
3: Classes of inhibitors/activators and their design
4: Clinically used agents or compounds in clinical development
5: Conclusion and outlook
References
Chapter 3.5: A disintegrin and metalloproteinases (ADAMs) and tumor necrosis factor-alpha-converting enzyme (TACE)
Abstract
1: General features of ADAMs
2: ADAM17
3: ADAM8
4: ADAM10
5: ADAM inhibitors
6: Conclusions
References
Chapter 3.6: Angiotensin-converting enzyme
Abstract
1: Structure and function of angiotensin-converting enzyme (ACE)
2: Physiologic/pathologic roles
3: Classes of modulators and their design
4: Clinically used agents or compounds in clinical development
Conflicts of interest
References
Chapter 3.7: Histidinol dehydrogenase
Abstract
1: Introduction
2: Structure and function of the enzyme HDH
3: Pathologic role of histidinol dehydrogenase
4: Classes of inhibitors and their design
5: Clinically used agents or compounds in clinical development
6: Conclusion
References
Chapter 3.8: Histone deacetylases and other epigenetic targets
Abstract
1: Introduction
2: Histone deacetylase (KDACs/KDACs)
3: Class I and II KDAC structures
4: Structure of sirtuins (Class III KDACs)
5: Class I and II KDACs mechanism on nucleosomal core histones
6: Catalytic mechanisms of sirtuins (Class III KDACs)
7: KDACs on nonhistone proteins
8: Zinc-dependent KDAC inhibitors (KDACis)
9: Sirtuin inhibitors
10: Conclusions
References
Chapter 3.9: CD73 (5′-Ectonucleotidase)
Abstract
1: Introduction
2: Mammalian 5′-nucleotidases
3: Bacterial 5′-nucleotidases
4: CD73 catalytic mechanism
5: Inhibitors of the human CD73 (hCD73)
6: Inhibitors of the bacterial CD73
7: Conclusions
References
Chapter 3.10: Glyoxalase II
Abstract
1: Introduction
2: The Glyoxalase System (GS)
3: Glyoxalase 2 enzymes (GLOs2)
4: Structural aspects of GLOs2
5: GLOs2 biological implications
6: Conclusions
References
Chapter 3.11: Glutamate carboxypeptidase II
Abstract
1: Introduction
2: GCP II biological localization
3: GCP II structure and reaction mechanism
4: GCP II inhibition
5: GCP II and diseases
6: Conclusions and perspectives
References
Chapter 3.12: Neutral endopeptidase (neprilysin)
Abstract
1: Structure and function of the enzyme
2: Physiologic/pathologic role
3: Classes of inhibitors and their design
4: Clinically used agents or compounds in clinical development
References
Section D: Other metalloenzymes
Chapter 4.1: The role of arginase in human health and disease
Abstract
1: Structure and function of the arginase isozymes
2: Physiologic and pathologic role associated to arginase
3: The development of arginase inhibitors and antibodies
4: Compounds and arginase formulation used in clinical development
References
Chapter 4.2: Methionine aminopeptidases
Abstract
1: Methionine aminopeptidases
References
Chapter 4.3: 1-Deoxy-d-xylulose 5-phosphate reductoisomerase, the first committed enzyme in the MEP terpenoid biosynthetic pathway—Its chemical mechanism and inhibition
Abstract
1: Chemical mechanism and intermediary of DXR
2: Substrate-binding mode
3: DXR catalytic cycle
4: DXR inhibitors
References
Section E: Nickel enzymes
Chapter 5.1: Urease
Abstract
1: Introduction
2: Structure and function
3: Physiological roles and involvement in diseases
4: Insight into the dual urease-carbonic anhydrase enzyme system in H. pylori
5: Urease as a diagnostic tool for H. pylori infections
6: Urease as pharmacological target: Design and development of inhibitors
References
Chapter 5.2: Methyl-coenzyme M reductase
Abstract
1: Methyl-coenzyme M reductase: An important biocatalyst complex in archaea metabolism
2: Phylogenetic and cellular localization of MCRs
3: Conformations of MCR and oxidation states of the coenzyme F430 nickel atom
4: Coenzyme F430
5: The MCR isoforms
6: Structural features of MCRs
7: Posttranscriptional modifications
8: Catalytic mechanism of MCRs
9: Catalytic features of MCRs
10: MCR inhibitors
11: Conclusions
References
Section F: Iron enzymes (heme-containing)
Chapter 6.1: Cyclooxygenase
Abstract
1: Introduction
2: Structure and function of the enzyme
3: Physiological and pathological role
4: Classes of modulators
5: Design of inhibitors
6: Clinically used agents and compounds in clinical development
References
Chapter 6.2: Cytochrome P450 (inhibitors for the metabolism of drugs)
Abstract
1: Introduction
2: Structure and function
3: Physiology and pathophysiology
4: Classes of inhibitors/activators and their design
5: Conclusion
References
Chapter 6.3: Aromatase
Abstract
1: Introduction
2: Structure and function
3: Physiology and pathophysiology
4: Classes of inhibitors/activators
5: Clinically used agents or compounds in clinical development
References
Section G: Iron enzymes, non-heme containing
Chapter 7.1: Nonheme mono- and dioxygenases
Abstract
1: Introduction
2: Pterin-dependent monooxygenases
3: Ring cleaving dioxygenases
4: 2-Oxoglutarate-dependent dioxygenases
5: 4-Hydroxyphenylpyruvate dioxygenase
6: Crystal structures of 4-hydroxyphenylpyruvate dioxygenase
7: Catalytic mechanism of 4-hydroxyphenylpyruvate dioxygenase
8: Classes of HPPD inhibitors: Triketones, pyrazoles, and isoxazoles
9: Disorders associated with tyrosine metabolism
10: Therapeutical uses of NTBC and other human HPPD inhibitors
References
Chapter 7.2: Indoleamine 2,3-dioxygenase
Abstract
1: Introduction
2: Discovery of IDO
3: Gene, structure and catalytic mechanism of IDO
4: IDO1 expression in tissues and expression regulation
5: Physiological functions and involvement in diseases of IDO
6: Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase 2 (IDO2)
7: IDO inhibitors
8: Conclusions
References
Section H: Copper enzymes
Chapter 8.1: Superoxide dismutases inhibitors
Abstract
1: Introduction
2: Structure and catalytic mechanism of SOD isoforms
3: The roles of SODs in human diseases
4: SOD inhibitors
5: Future perspectives
References
Chapter 8.2: Tyrosinase enzyme and its inhibitors: An update of the literature
Abstract
1: Introduction
2: Structure and function of the enzyme
3: Physiological/pathological role
4: Tyrosinase as pharmacological target: design and development of inhibitors
5: Clinically used agents or compounds in clinical development: An update of the literature
References
Section I: Cadmium enzymes CAs
Chapter 9: CDCA1, a versatile member of the ζ-class of carbonic anhydrase family
Abstract
1: Introduction
2: Biochemical features, CO2 hydration activity and its modulation
3: Structural features: Overall fold, substrate binding pocket, and access route
4: From structure to function: ζ-CAs show CS2 hydrolase activity
5: Conclusions and future perspectives
References
Section J: Molybdenum enzymes
Chapter 10: Molybdenum enzymes
Abstract
1: Introduction
2: The molybdenum cofactor (Moco)
3: Moco enzymes
4: Molybdenum cofactor deficiencies (MoCD)
References
Section K: Tungsten-containing enzymes
Chapter 11: Tungsten-containing enzymes
Abstract
1: Introduction
2: Tungsten an ancestral precursor of molybdenum
3: Tungsten-containing enzymes
4: Aldehyde ferredoxin oxidoreductase (AOR)
5: Formaldehyde ferredoxin oxidoreductase (FOR)
6: Glyceraldehyde-3-phosphate ferredoxin oxidoreductase (GAPOR)
7: Carboxylic acid reductase (CAR)
8: Aldehyde dehydrogenase (ADH)
9: Formate dehydrogenase (FDH)
10: N-formylmethanofuran dehydrogenase (FMDH)
11: Acetylene hydratase (AH)
12: Tungstoenzymes and human health
13: Conclusion
References
Index

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health

Metalloenzymes

From Bench to Bedside

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Claudiu T. Supuran

William Alexander Donald