Hydrogen Sulfide E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: Wiley series in drug discovery and development
- Sprache: Englisch
HYDROGEN SULFIDE Covers H2S interactions, methods of detection and delivery in biological environments, and a wide range of applications Research on hydrogen sulfide (H2S) spans diverse disciplines including chemistry, biology, and physiology. In recent years, new materials and approaches have been developed to deliver H2S and related reactive sulfur species in various clinical contexts. Although many biological pathways involving H2S are complex, all are governed by fundamental chemical interactions between reactive sulfur species and other molecular entities. Hydrogen Sulfide: Chemical Biology Basics, Detection Methods, Therapeutic Applications, and Case Studies provides the foundation required for understanding the fundamental chemical biology of H2S while highlighting the compound's therapeutic potential and medicinal applications. This book covers key aspects of H2S chemical biology, including the fundamental chemistry of reactive sulfur species; the measurement, detection, and delivery of H2S in biological environments; and the therapeutic and medicinal uses of exogenous H2S delivery in various pharmacologically relevant systems. Throughout the text, editor Michael Pluth and chapter contributors discuss the opportunities and future of the multidisciplinary field. * Provides approaches for delivering H2S with relevance to biological and therapeutic applications * Describes complex interactions of H2S with bioinorganic complexes and reactive sulfur, nitrogen, and oxygen species * Summarizes advances in available tools to detect, measure, and modulate H2S levels in biological environments, such as real-time methods for H2S fluorescence imaging in live cell and animal systems * Helps readers understand known systems and make connections to new and undiscovered pathways and mechanisms of action * Includes in-depth case studies of different systems in which H2S plays an important role Hydrogen Sulfide: Chemical Biology Basics, Detection Methods, Therapeutic Applications, and Case Studies is an important source of current knowledge for researchers, academics, graduate students, and industrial scientists in the fields of redox biology, hydrogen sulfide research, and medicinal chemistry of small biological molecules.
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Table of Contents
Cover
Title Page
Copyright
Preface
List of Contributors
1 Fundamental and Biologically Relevant Chemistry of H
2
S and Related Species
List of Abbreviations
1.1 Introduction
1.2 The Chemical Biology of H
2
S
1.3 H
2
S Reactions with Other Sulfur Species
1.4 The Biochemical Utility of RSSH
1.5 Summary/Conclusion
References
2 Signaling by Hydrogen Sulfide (H
2
S) and Polysulfides (H
2
S
n
) and the Interaction with Other Signaling Pathways
List of Abbreviations
2.1 Introduction
2.2 Determination of the Endogenous Concentrations of H
2
S
2.3 H
2
S and H
2
S
n
as Signaling Molecules
2.4 Crosstalk Between H
2
S and NO
2.5 Cytoprotective Effect of H
2
S, H
2
S
n
, and H
2
SO
3
2.6 Energy Formation in Mitochondria with H
2
S
2.7
S
‐Sulfurated Proteins and Bound Sulfane Sulfur in Cells
2.8 Regulating the Activity of Target Proteins by H
2
S and H
2
S
n
2.9 Perspectives
Acknowledgments
Author Disclosure Statement
References
3 Persulfides and Their Reactions in Biological Contexts
List of Abbreviations
3.1 Persulfides Are Key Intermediates in Sulfur Metabolism and Signaling
3.2 Persulfides Are Formed in Biological Systems through Different Pathways
3.3 Persulfides Are More Acidic Than Thiols
3.4 Persulfides Are Stronger Nucleophiles Than Thiols
3.5 Persulfidation Protects Against Irreversible Oxidation
3.6 Persulfides Interact with Metals and Metalloproteins
3.7 Persulfides Have Electrophilic Character in Both Sulfur Atoms
3.8 Persulfides Are Efficient One‐Electron Reductants
3.9 Concluding Remarks
References
Notes
4 Hydrogen Sulfide, Reactive Nitrogen Species, and “The Joy of the Experimental Play*”
4.1 Introduction
4.2 Basic Physicochemical Properties of Nitric Oxide and Its Biological Relevant Metabolites
4.3 Basic Physicochemical Properties of H
2
S and Its Biological Relevant Metabolites
4.4 Inorganic Sulfur–Nitrogen Compounds
4.5 Putative Biological Relevance of the NO/H
2
S Chemical Interaction
4.6 Summary and Conclusions
Acknowledgment
References
Note
5 H
2
S and Bioinorganic Metal Complexes
List of Abbreviations
5.1 Introduction
5.2 Basic Ligative Properties of H
2
S/HS
−
5.3 H
2
S and Heme Iron
5.4 H
2
S and Nonheme Iron
5.5 H
2
S Chemistry with Other Metals
5.6 H
2
S Sensing with Transition Metal Complexes
5.7 Summary
Acknowledgments
References
6 Measurement of Hydrogen Sulfide Metabolites Using the Monobromobimane Method
List of Abbreviations
6.1 Introduction
6.2 Monobromobimane: An Optimal Method of Bioavailable Sulfur Detection
6.3 Procedures
6.4 Caveats and Considerations
Acknowledgment
Disclosures
References
7 Fluorescent Probes for H
2
S Detection: Cyclization‐Based Approaches
List of Abbreviations
7.1 Introduction
7.2 General Design of Nucleophilic Reaction‐Cyclization Based Fluorescent Probes
7.3 Conclusions and Perspectives
Acknowledgments
References
8 Fluorescent Probes for H
2
S Detection: Electrophile‐Based Approaches
8.1 Introduction
8.2 Selected Probes Based on Different Reaction Types
8.3 Conclusion and Future Prospects
References
9 Fluorescent Probes for H
2
S Detection: Metal‐Based Approaches
9.1 Introduction
9.2 Metal Displacement Approach
9.3 Coordinative‐Based Approach
9.4 H
2
S‐Mediated Reduction of the Metal Center
9.5 Conclusions and Future Outlooks
References
10 H
2
S Release from PS and SeS Motifs
List of Abbreviations
10.1 Introduction
10.2 H
2
S Release from P
S Motifs
10.3 H
2
S Release from SeS Motifs
10.4 Acyl Selenylsulfides: Structural Modifications and Activity of Analogs
10.5 Conclusions
References
11 Hydrogen Sulfide: The Hidden Player of Isothiocyanates Pharmacology
11.1 Organic Isothiocyanates as H
2
S‐Donors
11.2 Organic ITCs and Cardiovascular System
11.3 Chemopreventive Properties of ITCs
11.4 Anti‐nociceptive Effects of ITCs
11.5 Anti‐inflammatory and Antiviral Effects of ITCs
11.6 Conclusion
Acknowledgment
References
12 Persulfide Prodrugs
List of Abbreviations
12.1 Introduction
12.2 Persulfide Prodrugs
12.3 Challenges in Persulfide Prodrug Design and Potential Therapeutic Applications
References
13 COS‐Based H
2
S Donors
13.1 Introduction
13.2 Properties of COS
13.3 COS‐Based H
2
S Delivery
13.4 Conclusions and Outlook
Acknowledgments
References
14 Light‐Activatable H
2
S Donors
14.1 Introduction
14.2 Photophysical and Photochemical Concepts
14.3 Phototherapeutic Window
14.4 Light Sources
14.5 (Photo)Physical Properties of H
2
S
14.6 Mechanisms and Examples of H
2
S Photorelease
14.7 Outlook
Acknowledgment
References
15 Macromolecular and Supramolecular Approaches for H
2
S Delivery
List of Abbreviations
15.1 Introduction
15.2 H
2
S‐Donating Linear Polymers
15.3 H
2
S Delivery from Branched and Graft Polymer Topologies
15.4 Polymer Micelles for H
2
S Delivery
15.5 Polymer Networks for Localized H
2
S Delivery
15.6 Other Polymeric Systems for the Encapsulation of H
2
S Donors
15.7 H
2
S Release via Supramolecular Systems
15.8 Conclusions and Future Perspectives
References
16 H
2
S and Hypertension
List of Abbreviations
16.1 Hypertension, Vascular Homeostasis and Mediators Controlling Blood Pressure
16.2 Generation of H
2
S in the Cardiovascular System
16.3 Relevance of H
2
S in Hypertension
16.4 Conclusions
References
17 H
2
S Supplementation and Augmentation: Approaches for Healthy Aging
List of Abbreviations
17.1 Introduction and Background
17.2 Hydrogen Sulfide Metabolism and Applications in Non‐mammalian Aging
17.3 Hydrogen Sulfide Metabolism and Applications in Nonhuman Mammalian Aging
17.4 Hydrogen Sulfide Metabolism and Applications in Human Aging and Aging‐Related Disorders
17.5 Conclusions and Summary
Acknowledgments
References
18 Aberrant Hydrogen Sulfide Signaling in Alzheimer's Disease
List of Abbreviations
18.1 Introduction
18.2 Alzheimer's Disease
18.3 Therapeutic Avenues
Acknowledgments
References
19 Multifaceted Actions of Hydrogen Sulfide in the Kidney
List of Abbreviations
19.1 Introduction
19.2 H
2
S Synthesis in the Kidney
19.3 H
2
S and Kidney Physiology
19.4 H
2
S and the Aging Kidney
19.5 H
2
S and Acute Kidney Injury (AKI)
19.6 H
2
S in Chronic Kidney Disease (CKD)
19.7 H
2
S and Preeclampsia
19.8 H
2
S and Genitourinary Cancers
19.9 Conclusion and Future Directions
Acknowledgments
References
Index
End User License Agreement
List of Tables
Chapter 10
Table 10.1 Synthesis and
31
P NMR chemical shifts (DMSO‐
d
6
) of phosphorodithi...
Table 10.2 Synthesis and
31
P NMR chemical shifts (CDCl
3
) of cyclized donors ...
Chapter 17
Table 17.1 H
2
S‐derivatized drugs and their protection from GI toxicity.
List of Illustrations
Chapter 1
Figure 1.1 Redox relationship of biologically relevant sulfur species (R = a...
Figure 1.2 Some sulfheme structures generated via H
2
S/oxidizing conditions....
Chapter 2
Figure 2.1 Acid‐labile sulfur releases H
2
S under acidic conditions. Iron–sul...
Figure 2.2 TRPA1 channels are activated by S‐sulfuration of two cysteine res...
Figure 2.3 Products from the chemical interaction of H
2
S and NO. The chemica...
Figure 2.4 Bound sulfane sulfur, which releases H
2
S under reducing condition...
Figure 2.5 S‐Sulfuration (S‐sulfhydration) of cysteine residues of target pr...
Chapter 3
Figure 3.1 Acidity and reactivity of persulfides: Hydropersulfides (RSSH) de...
Figure 3.2 Biochemical pathways of persulfide formation: H
2
S can react with ...
Figure 3.3 Fraction of deprotonated species versus pH for GSSH and GSH: The ...
Figure 3.4 Alpha effect of persulfides: Brønsted plot for the reactions of s...
Chapter 4
Figure 4.1 Reactivity of HSNO formed by and HS
−
: isomerization, homoly...
Figure 4.2 Isomerization of SNO
−
into NSO
−
via formation of a cy...
Chapter 5
Figure 5.1 Top: Formation of a sulfheme from an oxyheme and H
2
S highlighting...
Figure 5.2 Structure of the active site of HbI‐sulfide from
L. pectinata
(PD...
Figure 5.3 Structure of human Hb‐sulfide (PDB code: 5UCU).
Figure 5.4 Top: Representative reaction for the formation of iron(II) hydros...
Figure 5.5 Structure of HydG monomer B from
Thermoanaerobacter italicus
(PDB...
Figure 5.6 Transformations of nitrosyliron species containing hydrosulfide l...
Figure 5.7 Reversible binding of H
2
S to a nonheme iron(II) compound and the ...
Figure 5.8 Top: Picture of the hydrosulfide‐bound XOR intermediate. Bottom: ...
Figure 5.9 Structure of the active site of sulfide‐bound Co‐PDF from
E. coli
Scheme 5.1 Ferric hydrosulfide complexes of semisynthetic heme complexes.
Scheme 5.2 Hydrosulfide‐bound [Fe
4
S
4
] cluster of RimO.
Scheme 5.3 Synthesis of biomimetic [Fe
4
S
4
] clusters with terminal HS
−
...
Scheme 5.4 Synthetic site‐differentiated [Fe
4
S
4
] clusters featuring hydrosul...
Scheme 5.5 Heterometallic iron‐sulfur clusters with HS
−
ligands.
Scheme 5.6 Generation of H
2
S during iron‐sulfur cluster disassembly.
Scheme 5.7 Thiol desulfurization with bimetallic iron(II) species.
Scheme 5.8 Reactions of Tp
R
Zn complexes with H
2
S.
Scheme 5.9 Other Zn hydrosulfide complexes.
Scheme 5.10 Stabilization of a Zn(II) hydrosulfide complex by hydrogen‐bondi...
Scheme 5.11 Formation of hydrosulfide complexes in a XOR mimic.
Scheme 5.12 Sulfide detection with metal PPIX complexes.
Scheme 5.13 Hydrosulfide detection with [Zn(TmPyP)]
4+
.
Scheme 5.14 Phthalocyanine‐based approaches for sulfide detection.
Scheme 5.15 Hydrosulfide detection with a Zn salen complex.
Scheme 5.16 Sulfide detection by fluorophore displacement.
Chapter 6
Figure 6.1 Bioavailable sulfide: free sulfide, acid‐labile sulfide, and boun...
Figure 6.2 Schematic representation of the derivatization of hydrogen sulfid...
Chapter 7
Scheme 7.1 (a) Proposed reactivity difference between H
2
S and thiols. (b) Ge...
Scheme 7.2 (a) Fluorescence turn‐on mechanism of WSP1 as the example. (b) Re...
Scheme 7.3 (a) Structures of NIPY‐PBA and EW‐H. (b) Structures of selected N...
Scheme 7.4 2,2′‐Dithiosalicylic ester‐based probes for H
2
S detection.
Scheme 7.5 Alkyl halide‐based probes for H
2
S detection.
Scheme 7.6 Diselenide‐based probes for H
2
S detection.
Scheme 7.7 Selenenyl sulfide‐based probes for H
2
S detection.
Scheme 7.8 Aldehyde addition‐based probes for H
2
S using a tandem aldehyde ad...
Scheme 7.9 Aldehyde addition‐based probes proposed to function through –SH m...
Scheme 7.10
O
‐Carboxybenzaldehyde‐based probes for H
2
S detection.
Scheme 7.11 Michael addition cyclization‐based probes for H
2
S.
Scheme 7.12 Michael addition cyclization‐based probes that generate a ratiom...
Chapter 8
Figure 8.1 (a–d) Dissociation reactions for three biothiols (Cys, Hcy, and G...
Figure 8.2 (a–d) Four kinds of chemical reactions using for the development ...
Figure 8.3 (a) Chemical structure of probe
1
and its reaction with H
2
S. (b) ...
Figure 8.4 (a) A phosphorescence response mechanism of
3
toward H
2
S. (b) Vis...
Figure 8.5 (a) Chemical structure of probe
4
and its reaction with H
2
S. (b) ...
Figure 8.6 (a) Chemical structures of
5
and
6
and their reactions with H
2
S. ...
Figure 8.7 (a–c) Chemical structures of probes
7
–
9
and their reactions with ...
Figure 8.8 (a–c) Chemical structures of probes
10
–
12
and their reversible re...
Figure 8.9 (a) Inclusion of cationic charge in the system enables access to ...
Figure 8.10 (a) Chemical structure of probe
13
and its reaction with H
2
S. (b...
Figure 8.11 (a) Chemical structure of probe
14
and its reaction with H
2
S and...
Figure 8.12 The reaction mechanism of H
2
S‐mediated reduction of aryl azide
1
...
Chapter 9
Figure 9.1 Working mechanism for compound (
7
).
Figure 9.2 Imidazole and benzimidazole‐based copper complexes for H
2
S sensin...
Figure 9.3 Rhodamine‐based systems for Cu
2+
‐mediated H
2
S sensing.
Figure 9.4 Schiff‐base copper‐containing systems for H
2
S sensing.
Figure 9.5 Schiff‐base zinc systems for H
2
S detection.
Figure 9.6 Hydrosulfide bound to Co‐PDF (hydrosulfide in black and water in ...
Figure 9.7 Recognition mechanism of H
2
S by
41
.
Figure 9.8 Recognition mechanism of H
2
S by
42
.
Chapter 10
Figure 10.1 A summary of the major physiological and pharmacological effects...
Figure 10.2 Structures of
O
‐substituted
N
‐phenyl phosphorodithioate‐based H
2
Figure 10.3 Relationship between
31
P NMR chemical shift and H
2
S production f...
Figure 10.4 Reported IC
50
(μM) values for cell growth inhibition of compound...
Figure 10.5 Phosphorodithioate‐based donors in order of increasing H
2
S produ...
Figure 10.6 Recently reported phosphorothioate‐based donors that undergo cyc...
Scheme 10.1 General reaction involving LR as a sulfurization reagent in orga...
Scheme 10.2 Synthesis of GYY4137.
Scheme 10.3 Two‐step hydrolysis of GYY4137 as outlined by Alexander and cowo...
Scheme 10.4 Synthesis of useful control compounds (
3
and ZYJ1122) for studie...
Scheme 10.5 Hydrolysis products of dibutyldithiophosphate.
Scheme 10.6 A red light activated H
2
S donor. Coordination of GYY4137 to a ph...
Scheme 10.7 Structures of JK donors along with their putative mechanism for ...
Scheme 10.8 Release of persulfides from acyl disulfide precursors.
Scheme 10.9 Synthesis of acyl selenylsulfides.
Scheme 10.10 Degradation products of
37a
while exposed to (a) excess cystein...
Scheme 10.11 Putative mechanism for H
2
S release from acyl selenylsulfides wh...
Scheme 10.12 Observed reactivity of cyclic acyl selenylsulfides in the prese...
Chapter 11
Figure 11.1 The reaction shows the mechanism leading to the formation of the...
Figure 11.2 The reaction shows the formation of ITC adducts with cysteine th...
Figure 11.3 Structures of the main isothiocyanates discussed in the chapter....
Figure 11.4 Schematic representation of the beneficial effects exhibited by ...
Figure 11.5 Cysteine‐dependent H
2
S‐release is responsible for the antioxidan...
Figure 11.6 H
2
S‐mediated anti‐inflammatory effects of ITCs. (A) ITCs release...
Chapter 12
Figure 12.1 Strategies to deliver persulfide species.
Figure 12.2 Various examples of chemical methods for releasing persulfide sp...
Figure 12.3 Esterase‐sensitive persulfide prodrugs. (a) Esterase‐promoted pe...
Figure 12.4 Enzyme‐sensitive persulfide and H
2
S
2
prodrugs utilizing a “trime...
Figure 12.5 ROS‐sensitive persulfide prodrugs. (a) A ROS‐sensitive NAC persu...
Figure 12.6 pH‐sensitive persulfide species (a) and H
2
S
2
(b) prodrugs via “h...
Figure 12.7 pH‐sensitive persulfide prodrugs. (a) pH‐sensitive persulfide pr...
Figure 12.8 Light‐sensitive prodrugs for (a) NAC persulfide and (b) H
2
S
2
.
Figure 12.9 H
2
S prodrugs that release H
2
S via a persulfide intermediate. (a)...
Figure 12.10 Degradation of persulfide prodrug in the presence of free thiol...
Chapter 13
Figure 13.1 Hydrothermal generation of dipeptides in the presence of CO, (Ni...
Figure 13.2 Self‐immolation cascade reaction of caged thiocarbamates. Deprot...
Figure 13.3 Analyte‐replacement H
2
S probe mechanism of COS/H
2
S release with ...
Figure 13.4 Mechanism of ROS‐activation of aryl boronates and representative...
Figure 13.5 Click‐and‐release mechanism of TCO‐1 to produce COS/H
2
S.
Figure 13.6 Light‐activated COS/H
2
S release of PhotoTCM‐1.
Figure 13.7 Representative light‐activated COS‐based H
2
S donors.
Figure 13.8 Example NTA‐based COS/H
2
S donors and the associated mechanism of...
Figure 13.9 Cysteine‐selective activation of OA‐CysTCM‐1.
Figure 13.10 Proposed COS/H
2
S release pathways from SulfenylTCM donors.
Figure 13.11 DTS mechanism of COS/H
2
S release with alternative direct H
2
S re...
Figure 13.12 Proposed alternative pathway for COS‐based H
2
S release from 1,2...
Figure 13.13 Persulfide and COS releasing pathways of
N
‐alkyl perthiocarbama...
Figure 13.14 (a)
t
‐Butyl esterase donors with a methylenedioxy linker. (b) C...
Figure 13.15 NQO1‐mediated COS/H
2
S release of NQO1 donors.
Figure 13.16 Proposed mechanism of pH‐dependent release of
S
‐pHTCM and pH cu...
Figure 13.17 Mechanism of COS/H
2
S release from γ‐KetoTCM‐1.
Figure 13.18 COS/H
2
S release and simultaneous turn on fluorescence of FLD in...
Figure 13.19 Fluorescent COS‐based H
2
S donors.
Chapter 14
Figure 14.1 Jabłonski diagram.
Figure 14.2 Naphthalimide‐substituted H
2
S donor
21
.
Scheme 14.1 Mechanisms of the photoinduced release of H
2
S.
Scheme 14.2 Photoactivatable thiolated malachite green as a monoprotected H
2
Scheme 14.3 Photo‐Favorskii rearrangement.
Scheme 14.4 Doubly protected H
2
S with two pHP groups.
Scheme 14.5 Doubly protected H
2
S with two
m
‐aminobenzyl groups.
Scheme 14.6 Photochemistry of oNB group.
Scheme 14.7 Doubly protected H
2
S with two oNB groups.
Scheme 14.8 Doubly protected H
2
S with two ketoprofenate groups.
Scheme 14.9 The photochemical production of thiocarbamate as an H
2
S donor us...
Scheme 14.10 BODIPY‐based H
2
S donor and the mechanism of its photoactivation...
Scheme 14.11 The
meso
‐methyl‐substituted BODIPY‐based H
2
S‐releasing molecule...
Scheme 14.12 Photorelease of
gem
‐dithiols as H
2
S donors.
Scheme 14.13
o
‐Nitrobenzyl caged
gem
‐dithiols and the mechanism of their dep...
Scheme 14.14 Photorelease of thiobenzaldehyde as an H
2
S donor.
Scheme 14.15 Photorelease of phosphinodithioate as an H
2
S donor.
Scheme 14.16 Photosensitized H
2
S release.
Scheme 14.17 Photorelease of H
2
S from carbon dots decorated with quinoline‐b...
Scheme 14.18 (a) The release of H
2
S from nanocomposite hydrogel using photot...
Chapter 15
Figure 15.1 Release profile from different types of drug administration. The...
Figure 15.2 Functionalization methods for linear polymeric H
2
S donors. (a) P...
Figure 15.3 Types of copolymers: (a) block copolymer, (b) alternating copoly...
Figure 15.4 Chemical structure of PAEMA
10
‐
co
‐EGMA
60
, PAEMATK
10
‐
co
‐EGMA
60
, an...
Figure 15.5 (a) Chemical structure of POEGMA (R = CH
3
) and POEGA (R = H) wit...
Figure 15.6 Chemical structure of depolymerizable poly(thiourethane) to gene...
Figure 15.7 Types of branched and graft polymers. (a) Graft polymer topology...
Figure 15.8 Synthesis of poly(FBEMA‐
co
‐MEO
2
MA) polymers.
Figure 15.9 Chemical structures of OEGMA‐
block
‐M
1
and OEGMA‐
block
‐M
2
copolym...
Figure 15.10 Various types of drug loading either within or on polymer micel...
Figure 15.11 (a) PADT‐
block
‐PACMO. (b) (PADT‐
co
‐PTBAG)‐
block
‐PACMO copolymer...
Figure 15.12 Chemical structure of micelle forming polymers (a) (POEGMA‐
co
‐T...
Figure 15.13 Structure of (SATO‐
co
‐alkyl)‐
block
‐PEG polymer amphiphiles.
Figure 15.14 Methods of drug encapsulation within polymer networks. (a) Phys...
Figure 15.15 Library of PLA and PLGA polymers with various end groups.
Figure 15.16 Chemical structure of the crosslinked HA network doped with JK‐...
Figure 15.17 Peptide/SATO/PEG/CM‐cellulose hydrogel synthesis.
Figure 15.18 Micro scale polymeric drug delivery systems. (a) Polymeric micr...
Figure 15.19 Structure of electrospun NSHD1‐doped PCL microfibers.
Figure 15.20 Assembly of GaOS‐doped PFMs and DADS‐doped PFMs via electrospin...
Figure 15.21 Poly(lactic acid) 4‐hydroxythiobenzamide block copolymer (PLA‐4...
Figure 15.22 Chemical structures of AIE‐active PFHMA‐
graft
‐PEG and AIE‐activ...
Figure 15.23 Supramolecular nanostructures of H
2
S‐releasing peptides. (a) Tw...
Figure 15.24 (a) Structure of SATO‐functionalized peptide (IAVEEE). (b) Conv...
Figure 15.25 Chemical structure of SATO‐functionalized peptides with differe...
Figure 15.26 (a–c) Molecular structures of dSATO‐FE
4
, tSATO‐FE
4
, qSATO‐FE
4
(...
Figure 15.27 (a–c) Molecular structures of K
S
EK
S
E, K
S
K
S
EE, K
S
EEK
S
. (d–f) Cry...
Figure 15.28 (a) Molecular structure of AdK
S
K
S
EE. (b) Representative convent...
Figure 15.29 Synthesis of H
2
S‐donating spherical and worm‐like nanoparticles...
Figure 15.30 Schematic illustration of the formation of FeS@BSA nanoclusters...
Chapter 16
Figure 16.1 Schematic view of the role of H
2
S in the control of blood pressu...
Chapter 17
Figure 17.1 Growth of Global Population over age 65 by year 2050. Data used ...
Figure 17.2 Expansion of the global population percentage of those aged 65 a...
Figure 17.3 Endogenous H
2
S production pathways in mammalian systems. (a) Gen...
Figure 17.4 Current and future methods to treat and/or prevent aging‐related...
Figure 17.5 Trans‐sulfuration and H
2
S as central mediators for downstream be...
Chapter 18
Figure 18.1 Biosynthesis of hydrogen sulfide. H
2
S is generated via the rever...
Figure 18.2 Physiological functions of hydrogen sulfide. H
2
S modulates almos...
Figure 18.3 Isoforms of tau. Schematic representation of the six isoforms of...
Figure 18.4 Model depicting neuroprotective role of hydrogen sulfide in Alzh...
Chapter 19
Figure 19.1 Hydrogen sulfide synthesis in the kidney. A simplified schematic...
Figure 19.2 Hydrogen sulfide deficiency contributes to aging‐related kidney ...
Figure 19.3 Hydrogen sulfide deficiency participates in obesity‐associated k...
Guide
Cover Page
Title Page
Copyright
Preface
List of Contributors
Table of Contents
Begin Reading
Index
Wiley End User License Agreement
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Hydrogen Sulfide: Chemical Biology Basics, Detection Methods, Therapeutic Applications, and Case Studies, First Edition
Edited by Michael D. Pluth
Hydrogen Sulfide
Chemical Biology Basics, Detection Methods, Therapeutic Applications, and Case Studies
Michael D. Pluth
Department of Chemistry & BiochemistryUniversity of OregonEugene, OR, USA
This edition first published 2023
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Library of Congress Cataloging‐in‐Publication Data
Names: Pluth, Michael D., editor.
Title: Hydrogen sulfide : chemical biology basics, detection methods, therapeutic applications, and case studies / edited by Michael D. Pluth.
Description: First edition. | Hoboken, NJ : Wiley, 2022. | Series: Wiley series in drug discovery and development
Identifiers: LCCN 2022018103 (print) | LCCN 2022018104 (ebook) | ISBN 9781119799870 (cloth) | ISBN 9781119799894 (adobe pdf) | ISBN 9781119799887 (epub)
Subjects: LCSH: Hydrogen sulfide–Toxicology. | Hydrogen sulfide–Therapeutic use.
Classification: LCC RA1247.H8 H9325 2022 (print) | LCC RA1247.H8 (ebook) | DDC 615.9/1–dc23/eng/20220609
LC record available at https://lccn.loc.gov/2022018103
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Cover image: Courtesy of Michael D. Pluth
Preface
The last two decades have seen significant advances in our understanding of how reactive sulfur species affect biological systems. Of such species, hydrogen sulfide (H2S) has emerged as an important small molecule that now joins nitric oxide (NO) and carbon monoxide (CO) in a trio of “gasotransmitters” with broad impacts in various aspects of human health and disease. Why has Nature chosen to use these simple, reactive, typically toxic molecules to carry out complex and precise biological actions? The answer may be simple: In complex biological milieu, the heightened reactivity and affinity for specific targets, often manifested as toxicity at higher concentrations, are needed for the signal to rise above the noise. NO, CO, H2S, and emerging gasotransmitters all fit this paradigm – they are reactive small molecules that were initially recognized as toxic gasses but later found to be produced endogenously and exert biological action.
Growing from early initial observations of the potential role of H2S in neuromodulation, investigations into H2S now span diverse disciplines including chemistry, biology, physiology, and other adjacent fields. Although many biological pathways involving H2S are complex, all are governed by fundamental chemical interactions between reactive sulfur species and other molecular entities. Adding to this complexity, sulfur has a wide array of available redox states (−2 to +6), and H2S is the only canonical gasotransmitter with ionizable hydrogens. These properties provide simple pathways to modulate charge, lipophilicity, redox potential, and nucleophilicity – all of which contribute to the rich and rapidly expanding chemical biology of H2S. Understanding these systems and making connections to new, yet undiscovered pathways and mechanisms of action requires knowledge spanning different disciplines. One goal of this book is to provide a foundation for understanding the fundamental chemical biology of H2S to help bridge this gap between adjacent fields, while also highlighting selected applications and opportunities poised to advance this multidisciplinary area.
This book is divided into four main sections that cover key aspects of H2S chemical biology. The first section (Chapters 1–5) focuses on general concepts related to H2S and interactions with other reactive species in biological systems. These are the fundamentals – the key points needed to understand the complex interactions between H2S and other reactive biomolecules. The second section (Chapters 6–9) focuses on methods of measuring and detecting H2S in complex biological environments. These summarize key advances in available tools to ask the “where, when, and how much” type questions. The third section (Chapters 10–15) focuses on methods for delivering H2S in biological environments. These summarize key advances in available tools to modulate H2S levels in biological environments. The fourth and final section (Chapters 16–19) includes selected case studies on the role of H2S and H2S delivery related to human health. These highlight key opportunities for applications of H2S action in complex environments.
As the complex field of H2S chemical biology continues to advance and evolve, I hope that this book will provide a useful resource for students, researchers, and other professionals alike and help to inspire future work in this rapidly growing area.
Michael D. PluthOregon, USADecember, 2021
List of Contributors
Beatriz Alvarez
Laboratorio de Enzimología, Instituto de Química Biológica
Facultad de Ciencias, Universidad de la República
Montevideo
Uruguay
and
Centro de Investigaciones Biomédicas (CEINBIO)
Universidad de la República
Montevideo
Uruguay
Dayana Benchoam
Laboratorio de Enzimología, Instituto de Química Biológica
Facultad de Ciencias, Universidad de la República
Montevideo
Uruguay
and
Centro de Investigaciones Biomédicas (CEINBIO)
Universidad de la República
Montevideo
Uruguay
and
Graduate Program in Chemistry
Facultad de Química, Universidad de la República
Montevideo
Uruguay
Vincenzo Brancaleone
Department of Science
University of Basilicata
Potenza
Italy
Brock Brummett
Department of Chemistry
Brown University
Providence, RI
USA
Mariarosaria Bucci
Department of Pharmacy, School of Medicine
University of Naples Federico II
Naples
Italy
Giuseppe Cirino
Department of Pharmacy, School of Pharmacy
University of Naples Federico II
Naples
Italy
Valentina Citi
Department of Pharmacy
University of Pisa
Pisa
Italy
Miriam M. Cortese‐Krott
Myocardial Infarction Research Laboratory, Department of Cardiology, Pneumology, and Angiology, Medical Faculty
Heinrich Heine University
Düsseldorf
Germany
and
Department of Physiology and Pharmacology
Karolinska Institutet
Stockholm
Sweden
Ernesto Cuevasanta
Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias
Universidad de la República
Montevideo
Uruguay
and
Centro de Investigaciones Biomédicas (CEINBIO)
Universidad de la República
Montevideo
Uruguay
and
Unidad de Bioquímica Analítica, Centro de Investigaciones Nucleares, Facultad de Ciencias
Universidad de la República
Montevideo
Uruguay
Jon M. Fukuto
Department of Chemistry
Johns Hopkins University
Baltimore, MD
USA
and
Department of Chemistry
Sonoma State University
Rohnert Park, CA
USA
Annie K. Gilbert
Department of Chemistry and Biochemistry
Institute of Molecular Biology
Knight Campus for Accelerating Scientific Impact, Materials Science Institute, University of Oregon, Eugene
Oregon, 97403
USA
Rynne A. Hankins
Department of Chemistry
Wake Forest University
Winston‐Salem, NC
USA
Christopher Hine
Department of Cardiovascular and Metabolic Sciences
Cleveland Clinic Lerner Research Institute
Cleveland, OH
USA
Balakuntalam S. Kasinath
Department of Medicine, Center for Renal Precision Medicine
University of Texas Health
San Antonio, TX
USA
and
Barshop Institute for Longevity and Aging Studies
University of Texas Health
San Antonio, TX
USA
and
Geriatric Research, Education & Clinical Center
South Texas Veterans Health Care System
San Antonio, TX
USA
Christopher G. Kevil
Departments of Pathology and Translational Pathobiology
Molecular and Cellular Physiology and Cell Biology and Anatomy, LSU Health –Shreveport
Shreveport, LA
USA
Hideo Kimura
Department of Pharmacology, Faculty of Pharmaceutical Science
Sanyo‐Onoda City University
Sanyo‐Onoda, Yamaguchi
Japan
Petr Klán
Department of Chemistry, Faculty of Science
Masaryk University
Brno
Czech Republic
and
RECETOX, Faculty of Science
Masaryk University
Brno
Czech Republic
Yannie Lam
Department of Chemistry
Brown University
Providence, RI
USA
Hak Joo Lee
Department of Medicine, Center for Renal Precision Medicine
University of Texas Health
San Antonio, TX
USA
Zhao Li
Department of Chemistry
Virginia Polytechnic Institute and State University
Blacksburg, VA
USA
and
Macromolecules Innovation Institute
Virginia Polytechnic Institute and State University
Blacksburg, VA
USA
Christopher Link
Department of Cardiovascular and Metabolic Sciences
Cleveland Clinic Lerner Research Institute
Cleveland, OH
USA
Natalia Llarena
Department of Cardiovascular and Metabolic Sciences
Cleveland Clinic Lerner Research Institute
Cleveland, OH
USA
and
Department of Reproductive Endocrinology and Infertility
Cleveland Clinic Women's Health Institute
Cleveland, OH
USA
John C. Lukesh III
Department of Chemistry
Wake Forest University
Winston‐Salem, NC
USA
Alma Martelli
Department of Pharmacy
University of Pisa
Pisa
Italy
John B. Matson
Department of Chemistry
Virginia Polytechnic Institute and State University
Blacksburg, VA
USA
and
Macromolecules Innovation Institute
Virginia Polytechnic Institute and State University
Blacksburg, VA
USA
Caitlin McCartney
Department of Chemistry
Brown University
Providence, RI
USA
Matías N. Möller
Centro de Investigaciones Biomédicas (CEINBIO)
Universidad de la República
Montevideo
Uruguay
and
Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias
Universidad de la República
Montevideo
Uruguay
Bindu D. Paul
Department of Pharmacology and Molecular Sciences
Johns Hopkins University School of Medicine
Baltimore, MD
USA
and
Department of Psychiatry and Behavioral Sciences
Johns Hopkins University School of Medicine
Baltimore, MD
USA
and
The Solomon H. Snyder Department of Neuroscience
Johns Hopkins University School of Medicine
Baltimore, MD
USA
Claudio Pellecchia
Dipartimento di Chimica e Biologia
Università degli Studi di Salerno
Fisciano, SA
Italy
Eugenia Piragine
Department of Pharmacy
University of Pisa
Pisa
Italy
Michael D. Pluth
Department of Chemistry and Biochemistry
Institute of Molecular Biology
Knight Campus for Accelerating Scientific Impact, Materials Science Institute, University of Oregon, Eugene
Oregon, 97403
USA
Geat Ramush
Department of Chemistry
Brown University
Providence, RI
USA
Xinggui Shen
Departments of Pathology and Translational Pathobiology, LSU Health –Shreveport
Shreveport, LA
USA
Tomáš Slanina
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Prague
Czech Republic
Ellen H. Speers
LSU Health–Shreveport
Shreveport, LA
USA
Peter Štacko
Department of Chemistry
University of Zurich
Zurich
Switzerland
Maria Strianese
Dipartimento di Chimica e Biologia
Università degli Studi di Salerno
Fisciano, SA
Italy
Sarah N. Swilley‐Sanchez
Department of Chemistry
Virginia Polytechnic Institute and State University
Blacksburg, VA
USA
and
Macromolecules Innovation Institute
Virginia Polytechnic Institute and State University
Blacksburg, VA
USA
Zachary J. Tonzetich
Department of Chemistry
University of Texas at San Antonio
San Antonio, TX
USA
Binghe Wang
Department of Chemistry and Center for Diagnostics and Therapeutics
Georgia State University
Atlanta, GA
USA
Yingying Wang
Department of Chemistry
Brown University
Providence, RI
USA
Zhen Xi
Department of Chemical Biology, State Key Laboratory of Elemento‐Organic Chemistry
College of Chemistry, National Pesticide Engineering Research Center
Nankai University
Tianjin
China
Ming Xian
Department of Chemistry
Brown University
Providence, RI
USA
Jie Yang
Department of Cardiovascular and Metabolic Sciences
Cleveland Clinic Lerner Research Institute
Cleveland, OH
USA
Long Yi
Beijing University of Chemical Technology (BUCT)
College of Chemical Engineering
Beijing
China
Bingchen Yu
Department of Chemistry and Center for Diagnostics and Therapeutics
Georgia State University
Atlanta, GA
USA
Zhengnan Yuan
Department of Chemistry and Center for Diagnostics and Therapeutics
Georgia State University
Atlanta, GA
USA
Aili Zhang
Department of Cardiovascular and Metabolic Sciences
Cleveland Clinic Lerner Research Institute
Cleveland, OH, USA
1Fundamental and Biologically Relevant Chemistry of H2S and Related Species
Jon M. Fukuto
Department of Chemistry, Johns Hopkins University, Baltimore, MD, USA
Department of Chemistry, Sonoma State University, Rohnert Park, CA, USA
List of Abbreviations
RSH
Thiols
Cys-SH
Cysteine
Cys-SSH
cysteine hydropersulfide
Cys-SS-Cys
cystine
GSH
glutathione
GSSH
glutathione hydropersulfide
GSSG
oxidized glutathione
HSAB
hard-soft acid-base
HOMO
highest occupied molecular orbitals
LUMO
lowest unoccupied molecular orbitals
RSSR
disulfides
BDE
bond dissociation energy
RSSH
hydropersulfide
CcO
cytochrome coxidase
HbFeIII
ferric hemoglobin
HbFeII
ferrous hemoglobin
MbFeIII
ferric myoglobin
MbFeII
ferrous myoglobin
RS
alkylthiyl
MPO
myeloperoxidase
RSOH
sulfenic acid
RSNO
S-nitrosothiol
TEMPO
4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)oxyl
RSS
perthiyl radical
Sox
sulfur-oxidizing enzyme
1.1 Introduction
It is now evident that several endogenously synthesized di‐ and tri‐atomic molecules are important physiological bioregulators and/or signaling species (for a review of these molecules, see [1–3]). Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are all biosynthesized and reportedly possess important physiological signaling and regulatory functions. Since these molecules all exist as gasses at room temperature and pressure they have been grouped together under the term “gasotransmitters,” although they are solutes in biological media and not gases when they are acting physiologically. Dioxygen (O2), although not necessarily endogenously biosynthesized, can also be included in this group since it too (along with derived species) has biological signaling functions that are distinct from its role in cellular respiration. Importantly, as a group these signaling molecules likely represent an integrated signaling “web” due to the fact that they can share biological targets, can be involved in each other's biosynthesis, and for some even react with each other as either the parent molecule or via derived species. Thus, for a complete understanding of the chemical biology, mechanism of action and physiological functions of these signaling molecules it is important to consider them as an integrated group and not necessarily as individual species (e.g. [2, 4]). Among these molecules (i.e. NO, CO, O2, and H2S), H2S is distinct in that it has chemical properties and general reactivity not found in the others (vide infra). Clearly, the chemical biology is best defined and established for NO and, of course, O2. The chemical biology of H2S is much less understood and is therefore the focus of this chapter.
1.2 The Chemical Biology of H2S
As is the case with all biological effector species, the biological activity and/or utility of H2S are due to its chemical properties and chemical interactions with biological targets. In the context of this chapter, the term “chemical biology” refers to the chemical properties and reactivity of a species that are responsible for its biological actions. Therefore, an exhaustive and comprehensive discussion of all H2S chemistry is unwarranted and only the chemistry that is thought to be biologically relevant covered herein.
1.2.1 Basic Chemical Properties of H2S
Unlike the other small‐molecule signaling species (NO, CO, and O2), H2S is ionizable. The pKa's of H2S and HS− are 6.8 and 14, respectively. This indicates that at physiological pH (7.4), H2S is approximately 80% ionized to HS− with negligible amounts of the dianion S2−. H2S is the simplest of all thiols (RSH) and yet is somewhat distinct from them in that it is inherently more acidic. For example, the pKa values for most biologically relevant thiols (e.g. cysteine [Cys‐SH], glutathione [GSH]), free in solution are approximately 8.2. Thus, while most free thiols exist predominately as the protonated RSH species at physiological pH, H2S is mostly ionized. To be sure, the pKa of thiols in or attached to proteins can vary significantly due to effects associated with the protein environment (e.g. [5]). As a neutral molecule, H2S favorably partitions into nonpolar (e.g. lipid) environments as indicated by reported partition coefficients between H2O and organic solvents such as octanol or hexane of approximately 2 (indicating a twofold higher concentration of H2S in a hydrophobic/lipid environment versus a water environment) [6]. Thus, H2S can readily traverse membranes by simple diffusion. Of course, the charged, anionic HS− will not partition into nonpolar environments and therefore will not readily traverse membranes by diffusion. Thus, the rate of H2S diffusion will be highly dependent on the pH with acidic conditions favoring a more rapid diffusion. It is worthwhile to compare H2S and H2O with regard to their relative abilities to diffuse across membranes. The dipole moment for H2S is 0.97, while that for H2O is significantly greater at 1.84. Thus, H2S is distinct from H2O regarding its interaction with lipid, nonpolar environments. The diffusion of H2O across membranes is greatly dependent on the nature/composition of the membrane and occurs with a permeability coefficient in the range of 2–50 × 10−4 cm/s [7]. The permeability coefficient for H2S was found to be significantly greater at >0.5–3 cm/s [6, 8] indicating a much greater ability for H2S to diffuse across membranes compared to H2O. Importantly, unlike H2O diffusion across membranes, which can be greatly enhanced by aquaporins, H2S diffusion is relatively rapid and not enhanced by aquaporins [8].
The predominant biological chemistry of H2S is that of a Lewis base. That is, H2S (or more likely HS−) is an electron donor that reacts (forms bonds) with Lewis acids (i.e. electron acceptors). In organic chemistry terms, Lewis bases can be considered as nucleophiles and Lewis acids considered as electrophiles. Thus, HS− is an electron‐donating nucleophile capable of reacting with electron poor/deficient electrophilic centers. Of course, this is the chemical property that biological RSH species in general possess. One thing that sets H2S apart from all other RSH molecules is that it possesses two dissociable and exchangeable protons and therefore can potentially react twice with Lewis acids. Thus, the generation of complexes with bridging sulfides that connect two, for example, metal centers (i.e. M–S–M, M = metal) is very commonly seen. It is important to note, however, that Lewis bases/nucleophiles are not all equivalent with respect to their reactivity toward Lewis acids/electrophiles. One simple and useful way of distinguishing and rationalizing nucleophilic/electrophilic reactivity preferences is to utilize the Hard–Soft Acid Base (HSAB) principles developed by Pearson [9, 10]. The idea of HSAB relies on the characterization of Lewis bases and Lewis acids (i.e. nucleophiles and electrophiles) as being either soft or hard and the understanding that hard bases prefer to react with hard acids and soft bases prefer to react with soft acids. Of course, there are some reactants that are considered as “borderline” which can react either way. Generally speaking, soft bases/nucleophiles are qualitatively viewed as species with high polarizability, lower electronegativity, easily oxidized, and possessing low‐lying empty orbitals. Soft acids/electrophiles have an acceptor atom with low positive charge, large size, are polarizable, and possess easily excited outer electrons. On the other hand, hard bases have a donor atom with low polarizability, high electronegativity with high‐energy/inaccessible empty orbitals. Hard acids possess an acceptor atom with high‐positive charge, small size, and not polarizable. These reactivity preferences can also be reconciled on the basis of the energetics and nature of the reacting highest occupied molecular orbitals (HOMOs) of the base/nucleophile and the lowest unoccupied molecule orbitals (LUMOs) of the acid/electrophile (i.e. the Frontier orbitals) [11] with hard acid–hard base interactions viewed as primarily ionic in nature and soft acid–soft base interactions viewed as highly covalent in nature (due to favorable HOMO–LUMO overlap). Regardless, it is clear that RSH, RS−, H2S, and HS− are all soft bases/nucleophiles which readily predicts reaction with soft acids/electrophiles. H2S‐reactive and biologically relevant soft electrophiles include heavy metals (e.g. Cd2+, Hg2+), low oxidation state metals (e.g. Cu+), α–β unsaturated carbonyl compounds (e.g. acrolein, N‐ethylmaleimide) and disulfides (RSSR), among others. Importantly, the principles of HSAB also correctly reconcile the fact that RSSR electrophiles are not readily cleaved by hard nucleophiles such as H2O, HO−, NH3, or RNH2.
1.2.2 H2S Redox Chemistry
Numerous biologically relevant sulfur species with varying oxidation states have been reported and characterized (e.g. [12]) and of all these H2S (as well as thiols) represent the fully reduced sulfur species (Figure 1.1).
Thiols, including H2S, can potentially serve as one‐electron reductants, generating the radical intermediates (RS⋅/HS⋅). However, RS−/RSH and HS−/H2S are not powerful one‐electron reductants as indicated by the relatively high reduction potential for the RS⋅, H+/RSH, and HS⋅/HS− couples of approximately 0.92 V [13, 14]. Indeed, RS⋅ is known to be a potent oxidant generated at the active site of the enzyme ribonucleotide reductase capable of abstracting a hydrogen atom from the ribose ring of DNA (e.g. [15]). Thus, the fact that RS⋅ and HS⋅ are relatively strong oxidants generated from RS−/RSH or HS−/H2S oxidation indicates the weak one‐electron reducing capabilities of these species. Another indicator of the relatively weak one‐electron reducing capabilities of RSH/H2S are the S—H bond dissociation energies (BDEs) of approximately 87–92 kcal/mol [16, 17]. For comparison, the O—H BDE for tocopherol (e.g. vitamin E) is significantly lower (79 kcal/mol), indicating a higher propensity to serve as a reducing H‐atom donor.
Figure 1.1 Redox relationship of biologically relevant sulfur species (R = alkyl, H). The oxidation states of the sulfur atoms indicated by superscripted numerals.
1.2.3 Reactions of H2S with Metals/Metalloproteins
As alluded to above, H2S is a soft Lewis base and therefore reacts very readily with soft Lewis acid metals. Also, since H2S has two exchangeable protons, it has the potential to form two bonds to metal species, either to a single metal or bridging two metals. A prime example of sulfide (S2−) bridging can be found in iron–sulfur (FeS) cluster proteins. Although FeS clusters are very important and established biochemical entities involved in numerous functions including electron transfer processes, gene expression, oxygen sensing, regulation of enzymatic function and metal sensing, among many others (e.g. [18]), these will not be discussed further as there are numerous reviews of this topic available (e.g. [19, 20]). It is, however, worth mentioning that FeS biosynthesis involves the intermediacy of a hydropersulfide (RSSH), a functional group that will be discussed in some detail later.
The interactions of H2S with heme proteins is among the most studied, due in part to the fact that disruption of heme protein function (e.g. cytochrome c oxidase, CcO) is thought to contribute significantly to H2S‐mediated toxicity (e.g. [21]) and that heme proteins can also be involved in physiological H2S signaling, metabolism, and function [22]. The interactions of H2S with heme proteins, such as CcO, are potentially complex (e.g. [23]) and highly concentration‐dependent. At low levels, H2S can actually serve as a source of electrons, supporting oxidative phosphorylation [24, 25], an effect supported by a functional model system for CcO whereby low levels of H2S were capable of reducing both Fe and Cu sites of the model (as well as cytochrome c, which can donate electrons to CcO) [26]. However, at higher levels, H2S competes with O2 binding, possibly via binding to both the iron heme a3 and CuB centers of CcO [22] inhibiting respiration.
A particularly interesting interaction between H2S and a heme protein occurs with the specialized hemoglobin of Lucina pectinata, a mollusk that inhabits H2S‐rich environments. The hemoglobin of L. pectinata does not carry O2, but rather carries H2S as a source of electrons for symbiotic chemoautotrophic bacteria that inhabit its gills [27]. H2S can bind to and react with hemoglobin/myoglobin from other species (vide infra) often leading to oxidized H2S molecules. However, the stability of H2S bound to the hemoglobin of L. pectinata appears to be the result of a protective, hydrophobic pocket around the bound H2S that protects it against further chemistry [28–30]. With other globins such as hemoglobin or myoglobin, H2S binding can result in further reactions. For example, H2S binding to ferric hemoglobin (HbFeIII) or ferric myoglobin (MbFeIII) results in the catalytic oxidation of H2S to either thiosulfate or polysulfide species (e.g. HSnH, n > 1) via ferrous hemoglobin (HbFeII) or ferrous myoglobin (MbFeII) intermediates [31–33]. The reduction of FeIII to FeII by HS− has also been observed in model “picket‐fence” porphyrins as well [34]. Finally, Jensen and Fago [35] have examined the interactions of H2S with HbFeIII and MbFeIII at physiological concentrations and postulate that HbFeIII can act as an H2S carrier in blood, whereas MbFeIII may be involved in H2S metabolism. In the reduction of FeIII to FeII by H2S, a hydrothiyl (HS⋅) radical is thought to be generated, which can further react with H2S/HS− leading to the generation of polysulfide species (e.g. [31]). It is worth noting that the reaction of an alkylthiyl radical (RS⋅) with an alkylthiolate (RS−) is reported to give a disulfide radical anion [36], which is a potent reducing agent [37] capable of, for example converting O2 to superoxide (O2−). Whether the equivalent processes for HS⋅ and HS− are involved in the above reactions remain to be determined. Interestingly, another heme protein that is not involved in O2 transport or storage, myeloperoxidase (MPO), also reacts with H2S in chemistry that involves coordination of H2S/HS− to a ferric heme followed by possible redox chemistry generating ferrous protein and presumably HS⋅[38, 39]. As with the globins, HS⋅ generation can lead to polysulfur species. Peroxidatic chemistry of MPO also results in the oxidation of H2S to HS⋅ further contributing to the formation of polysulfurs.
1.2.4 H2S and Sulfheme Formation
As described above, the interaction of H2S/HS− with various hemeproteins results in redox chemistry that could result in HS⋅ intermediacy. Although HS⋅ in these systems can react with other sulfur molecules (giving, for example, thiosulfate or polysulfur species), it has also been proposed to react with the porphyrin ring of the heme protein, generating a modified heme species referred to as sulfheme (e.g. [40]). In sulfheme proteins, a sulfur atom is inserted into a pyrrole of the porphyrin ring (pyrrole B) under oxidizing conditions leading to a change in the absorbance (giving an absorbance at approximately 620 nm). Several distinct sulfheme isomers have been characterized (Figure 1.2) (e.g. [41]).
Figure 1.2 Some sulfheme structures generated via H2S/oxidizing conditions.
Source: Arbelo‐Lopez et al. [41]/American Chemical Society.
Currently, the exact mechanism of sulfheme formation is not established. However, it appears clear that H2S‐mediated sulfheme formation requires oxidizing conditions, consistent with the idea that H2S oxidation to HS⋅ may be a critical step. However, it should be noted that H2S‐independent sulfheme formation has been reported, possibly involving sulfenic acid (RSOH) or alkyl thiyl (RS⋅) species (e.g. [42]). Moreover, other oxidized H2S species such as RSSH and/or H2S2 have been implicated in sulfheme formation as well [43]. Regardless, sulfheme formation can alter the function/biochemistry of the heme protein. For example, the O2 affinities of myoglobin and hemoglobin are dramatically decreased when in the sulfheme form [44, 45] and sulfhemoglobin loses cooperative O2 binding [46].
1.2.5 H2S and Heavy Metals
As a soft Lewis base that preferentially reacts with soft Lewis acids, it is expected that H2S will rapidly react with heavy metal toxins such as Cd2+ and mercury species (e.g. methyl mercury, MeHg), forming stable complexes (many of which are known to precipitate). Indeed, H2S can be used as a reagent to precipitate and rid solutions of a variety of metal ions (e.g. [47]). It has been known for a long time that one strategy microbes utilize to gain resistance against heavy metal toxicity is via H2S generation [48]. For example bacterial resistance against mercury [49] and cadmium [50] toxicity has been linked to H2S‐biosynthetic capacity. This is also true in mammalian cells where exogenous H2S administration or increased H2S biosynthesis resulted in the detoxification of MeHg via the formation of the relatively nontoxic bis‐methylmercury sulfide ((MeHg)2S) [51]. In all of these cases, it is thought that H2S forms complexes with heavy metals (e.g. CdS, NiS, PbS) leading to nonreactive (and often insoluble) metal sulfides, thus protecting other biochemical thiol targets from being disrupted.
1.3 H2S Reactions with Other Sulfur Species
As mentioned earlier, H2S is the simplest of all thiols and as such can react in ways typical to other biological thiols. Some of the most prevalent and important reactions of biological thiols are those with other sulfur species. Thus, a discussion of this chemistry will be given.
1.3.1 Sulfane Sulfur
As will be addressed immediately below, when discussing biologically relevant H2S reactions with other sulfur species, there is the possibility of generating sulfane sulfur‐containing species. The term “sulfane sulfur” refers to a sulfur atom that is bonded only to other sulfur atoms [52]. For example, the bolded sulfur atoms of the following molecules are considered sulfane sulfurs since they are bonded only to other sulfur atoms: −S–S(O)2O− (thiosulfate), RSSSR (dialkyl trisulfide), RSSSSR (dialkyl tetrasulfide), and RSS− (hydropersulfide anion). Elemental sulfur (mostly S8) contains only sulfane sulfur atoms. In many molecules, the oxidation state of the sulfane sulfur is zero (S0) (e.g. RSS0SR, RSS0S0
