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Information on EC 1.8.5.8 - eukaryotic sulfide quinone oxidoreductase
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1.8.5.8 eukaryotic sulfide quinone oxidoreductaseIUBMB Comments
Contains FAD. This eukaryotic enzyme, located at the inner mitochondrial membrane, catalyses the first step in the metabolism of sulfide. While both sulfite and glutathione have been shown to act as sulfane sulfur acceptors in vitro, it is thought that the latter acts as the main acceptor in vivo. The electrons are transferred via FAD and quinones to the electron transfer chain. Unlike the bacterial homolog (EC 1.8.5.4, bacterial sulfide:quinone reductase), which repeats the catalytic cycle without releasing the product, producing a polysulfide, the eukaryotic enzyme transfers the persulfide to an acceptor at the end of each catalytic cycle.
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The enzyme appears in viruses and cellular organisms
Reaction Schemes
Synonyms
scsqr, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
HMT2
SQOR
SQR
Sqrdl
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-
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sulfide : quinone oxidoreductase
sulfide:quinone oxidoreductase
SQOR
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-
-
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SQR
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-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hydrogen sulfide + glutathione + a quinone = S-sulfanylglutathione + a quinol
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hydrogen sulfide + glutathione + a quinone = S-sulfanylglutathione + a quinol
mechanisms of protein persulfidation, overview
hydrogen sulfide + glutathione + a quinone = S-sulfanylglutathione + a quinol
proposed model for catalysis. The human SQOR reaction is initiated by nucleophilic attack of HS- at the distal cysteine, Cys379, to produce a charge-transfer (CT) complex of FAD with either Cys201S- or Cys379SS- (step 1). Nucleophilic attack of Cys201S- at the C(4a) position of FAD produces a covalent flavin adduct, 4a-adduct I (step 2). Reaction of 4a-adduct I with a sulfane sulfur acceptor (N:) generates 4a-adduct II and the thiolate form of Cys379 (step 3). Nucleophilic attack of Cys379S- at the sulfur atom in the 4a-adduct produces 1,5-dihydroFAD and regenerates the disulfide bridge (step 4). The catalytic cycle is completed upon transfer of electrons from 1,5-dihydro-FAD to CoQ
hydrogen sulfide + glutathione + a quinone = S-sulfanylglutathione + a quinol
the mechanism for sulfide oxidation is catalyzed by an active site cysteine trisulfide. SQR catalyzes two half reactions: (i) sulfur transfer from H2S to an acceptor via an active site cysteine persulfide (Cys-SSH) intermediate, and (ii) electron transfer from H2S to coenzyme Q10 (CoQ10) via an FADH2 intermediate. The first step in the proposed mechanism is addition of the sulfide anion to an active site disulfide between Cys201 and Cys379, generating a persulfide intermediate on Cys379 (379Cys-SSH) with concomitant release of the Cys201 thiolate. Formation of an electronic species is detected that is distinct from those seen in other members of the flavin disulfide reductase superfamily. In the final step, electron transfer to CoQ10 regenerates FAD and connects SQR to the electron transfer chain at the level of complex III. Reaction mechanism, overview
hydrogen sulfide + glutathione + a quinone = S-sulfanylglutathione + a quinol
the reaction cycle proceeds via two half reactions. In the first half reaction, sulfide adds to the trisulfide at the solvent-accessible Cys379 to form a 379Cys-SSH persulfide. The bridging sulfur is retained on 201Cys-SS- persulfide, which forms an unusually intense charge transfer (CT) complex with FAD. Sulfur transfer from 379Cys-SSH to a small molecule acceptor leads to regeneration of the active site trisulfide with the concomitant two-electron reduction of FAD. In the second half reaction, FADH2 transfers electrons to CoQ10, regenerating the resting enzyme and linking sulfide oxidation to mitochondrial energy metabolism by supplying reduced CoQ10 to Complex III in the electron transport chain
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
sulfide:glutathione,quinone oxidoreductase
Contains FAD. This eukaryotic enzyme, located at the inner mitochondrial membrane, catalyses the first step in the metabolism of sulfide. While both sulfite and glutathione have been shown to act as sulfane sulfur acceptors in vitro, it is thought that the latter acts as the main acceptor in vivo. The electrons are transferred via FAD and quinones to the electron transfer chain. Unlike the bacterial homolog (EC 1.8.5.4, bacterial sulfide:quinone reductase), which repeats the catalytic cycle without releasing the product, producing a polysulfide, the eukaryotic enzyme transfers the persulfide to an acceptor at the end of each catalytic cycle.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
hydrogen sulfide + CoA + coenzyme Q1
CoA-SSH + H+ + reduced coenzyme Q1
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-
-
?
hydrogen sulfide + coenzyme Q1
hydrogen disulfide + reduced coenzyme Q1
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-
-
?
hydrogen sulfide + glutathione + coenzyme Q1
glutathione persulfide + H+ + reduced coenzyme Q1
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-
-
?
hydrogen sulfide + glutathione + coenzyme Q1
S-sulfanylglutathione + reduced coenzyme Q1
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-
-
?
hydrogen sulfide + glutathione + coenzyme Q10
S-sulfanylglutathione + reduced coenzyme Q10
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-
-
?
hydrogen sulfide + glutathione + ubiquinone
S-sulfanylglutathione + ubiquinol
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-
-
ir
hydrogen sulfide + sulfite + coenzyme Q1
thiosulfate + reduced coenzyme Q1
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-
-
?
Na2S + glutathione + coenzyme Q1
S-sulfanylglutathione + reduced coenzyme Q1 + 2 Na+
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-
-
?
hydrogen sulfide + glutathione + a quinone
S-sulfanylglutathione + a quinol
-
-
-
?
hydrogen sulfide + glutathione + a quinone
S-sulfanylglutathione + a quinol
-
-
-
?
hydrogen sulfide + glutathione + a quinone
S-sulfanylglutathione + a quinol
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-
-
-
?
hydrogen sulfide + glutathione + a quinone
S-sulfanylglutathione + a quinol
-
-
-
?
hydrogen sulfide + glutathione + coenzyme Q
S-sulfanylglutathione + reduced coenzyme Q
-
-
-
?
hydrogen sulfide + glutathione + coenzyme Q
S-sulfanylglutathione + reduced coenzyme Q
-
-
-
ir
hydrogen sulfide + glutathione + decylubiquinone
S-sulfanylglutathione + decylubiquinol
-
-
-
?
hydrogen sulfide + glutathione + decylubiquinone
S-sulfanylglutathione + decylubiquinol
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-
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ir
hydrogen sulfide + glutathione + decylubiquinone
S-sulfanylglutathione + decylubiquinol
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-
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ir
hydrogen sulfide + glutathione + decylubiquinone
S-sulfanylglutathione + decylubiquinol
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-
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ir
hydrogen sulfide + glutathione + quinone
S-sulfanylglutathione + quinol
-
-
-
?
hydrogen sulfide + glutathione + quinone
S-sulfanylglutathione + quinol
-
-
-
ir
hydrogen sulfide + glutathione + quinone
S-sulfanylglutathione + quinol
-
-
-
ir
hydrogen sulfide + glutathione + quinone
S-sulfanylglutathione + quinol
-
-
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ir
additional information
?
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no activity with DHLA, cysteamine, coenzyme A, hypotaurine, cysteine sulfinic acid, and thioredoxin
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?
additional information
?
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under physiological conditions, the primary sulfane sulfur acceptor for the SQOR reaction is GSH, generating glutathione persulfide (GSSH) as the product. Substrate promiscuity leads to dead-end complexes. Human SQOR exhibits remarkable substrate promiscuity, and in addition to sulfide, a number of nucleophiles can add to the resting trisulfide. The addition of alternative nucleophiles to resting SQOR leads to the corresponding 379Cys mixed disulfide and the 201Cys-SS- persulfide that forms an intense charge transfer (CT) complex with FAD. Unlike the sulfide-induced CT complex, which decays quickly to yield FADH2, the alternative CT complexes represent dead-end complexes and decay slowly at rates that approximate the respective dissociation rate constants (koff) for the nucleophiles. Although these dead-end complexes could entrap SQOR in an unproductive state, their formation is suppressed to some extent by the membrane environment of SQOR
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additional information
?
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CoQ-binding pocket and substrate binding structures, overview. The entrance to the CoQ-binding pocket is located on the membrane-facing surface of human SQOR
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additional information
?
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SQOR accommodates alternative sulfane sulfur acceptors, e.g. small thiophilic acceptors. Structural basis for substrate promiscuity, overview
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additional information
?
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the rate of sulfide addition to the cysteine trisulfide of SQOR is estimated to much higher than the rate of sulfide addition to cysteine disulfide in solution. The subsequent formation of persulfide rather than thiolate intermediate on Cys201 also enhances its reactivity for facilitating sulfur transfer and electron movement via the putative C4a adduct. Computational modeling, overview
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additional information
?
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the substrate promiscuity of SQR is expanded to include CoA as an alternate sulfur acceptor, forming CoA-SSH. Postulation of a different mechanism for human SQR by assigning the 201Cys-SS- (versus the Cys201 thiolate) as the species involves in charge-transfer (CT) complex formation with FAD, and 379Cys-SSH as the sulfane sulfur donor to an external acceptor. Since the absorption spectrum of CoA interfers with monitoring CoQ1 reduction at 278 nm in the steady-state SQR assay, an alternative coupled assay is developed using persulfide dioxygenase (PDO), which oxidizes CoA-SSH in an O2-dependent reaction. Michaelis-Menten analysis of SQR activity at varying CoA concentrations, overview
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
hydrogen sulfide + glutathione + ubiquinone
S-sulfanylglutathione + ubiquinol
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-
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ir
additional information
?
-
under physiological conditions, the primary sulfane sulfur acceptor for the SQOR reaction is GSH, generating glutathione persulfide (GSSH) as the product. Substrate promiscuity leads to dead-end complexes. Human SQOR exhibits remarkable substrate promiscuity, and in addition to sulfide, a number of nucleophiles can add to the resting trisulfide. The addition of alternative nucleophiles to resting SQOR leads to the corresponding 379Cys mixed disulfide and the 201Cys-SS- persulfide that forms an intense charge transfer (CT) complex with FAD. Unlike the sulfide-induced CT complex, which decays quickly to yield FADH2, the alternative CT complexes represent dead-end complexes and decay slowly at rates that approximate the respective dissociation rate constants (koff) for the nucleophiles. Although these dead-end complexes could entrap SQOR in an unproductive state, their formation is suppressed to some extent by the membrane environment of SQOR
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hydrogen sulfide + glutathione + a quinone
S-sulfanylglutathione + a quinol
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?
hydrogen sulfide + glutathione + a quinone
S-sulfanylglutathione + a quinol
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-
-
?
hydrogen sulfide + glutathione + a quinone
S-sulfanylglutathione + a quinol
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-
-
-
?
hydrogen sulfide + glutathione + a quinone
S-sulfanylglutathione + a quinol
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-
-
?
hydrogen sulfide + glutathione + coenzyme Q
S-sulfanylglutathione + reduced coenzyme Q
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-
-
?
hydrogen sulfide + glutathione + coenzyme Q
S-sulfanylglutathione + reduced coenzyme Q
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ir
hydrogen sulfide + glutathione + quinone
S-sulfanylglutathione + quinol
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-
-
?
hydrogen sulfide + glutathione + quinone
S-sulfanylglutathione + quinol
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-
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ir
hydrogen sulfide + glutathione + quinone
S-sulfanylglutathione + quinol
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ir
hydrogen sulfide + glutathione + quinone
S-sulfanylglutathione + quinol
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-
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ir
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
molecular dynamics simulations and QM/MM reactivity predictors for a disulfide versus trisulfide cofactor involving FAD, overview
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FAD
required, FAD is noncovalently bound in an extended conformation and is in the oxidized state. The first Rossmann fold starts near the N-terminus and binds the ADP portion of FAD. The second Rossmann fold is closer to the isoalloxazine ring of FAD but is mostly positioned at least 10 A away from the flavin ring with one notable exception. FAD is bound in an extended conformation. Its interactions with the protein include 12 hydrogen bonds and electrostatic interactions with two helix dipoles. Two basic residues, Lys207 and Lys418, lie above the flavin's re- and si-face, respectively with their respective epsilon-amino groups 3.2 and 3.3 A from a carbonyl oxygen in the isoalloxazine ring (O4). Binding site structure, overview
FAD
the deduced ScSQR protein contains conserved FAD-binding domains, comprising residues 32-59, 121-134, and 306-331
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
cyanide
cyanide treatment destabilized human SQOR and leads to its inactivation with concomitant loss of the bridging sulfane sulfur. Addition of sulfide to inactive cyanide treated enzyme leads to recovery of active SQOR, indicating that the oxidation state of the active site cysteines is preserved upon cyanide treatment. Crystallization of SQOR with cyanide led to the capture of a 379Cys N-(201Cys-disulfanyl)-methanimido thioate intermediate. Spectral and kinetic characterization of cyanolysis-induced dismantling followed by sulfide-dependent rebuilding of the trisulfide cofactor, proposed mechanism for cyanolysis and cysteine trisulfide rebuilding in SQOR, overview
H2S
-
the enzyme activity decreases when the ambient sulfide concentration exceeds 0.3 mM
2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile
HTS12441
-
2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile
HTS12441
-
2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile
HTS12441
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2-methoxy-4-phenyl-5H-indeno[1,2-b]pyridine-3-carbonitrile
RH00520
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4-(2-chlorophenyl)-2-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile
HTS12442
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4-(2-chlorophenyl)-2-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile
HTS12442
-
4-(2-chlorophenyl)-2-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile
HTS12442
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4-(4-aminophenyl)-6-methoxy-3'-methyl[2,2'-bipyridine]-5-carbonitrile
STI1, SQOR-targeted inhibitor 1, STI1 is a potent and highly selective inhibitor of SQOR. The first-in-class inhibitor of sulfide:quinone oxidoreductase binds to the CoQ-binding pocket in human SQOR and protects against adverse cardiac remodeling and heart failure. Ability of STI1 to protect against pathological remodelling of the left ventricle and the progression to heart failure patients with reduced ejection fraction (HFrEF). Docking of STI1 to ligand-free SQOR (PDB ID 6M06) and modeling of the SQOR-STI1 complex
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4-(4-aminophenyl)-6-methoxy-3'-methyl[2,2'-bipyridine]-5-carbonitrile
STI1, SQOR-targeted inhibitor 1, STI1 is a potent and highly selective inhibitor of SQOR. The first-in-class inhibitor of sulfide:quinone oxidoreductase binds to the CoQ-binding pocket in SQOR and protects against adverse cardiac remodeling and heart failure
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4-(4-aminophenyl)-6-methoxy-3'-methyl[2,2'-bipyridine]-5-carbonitrile
STI1, SQOR-targeted inhibitor 1, STI1 is a potent and highly selective inhibitor of SQOR. STI1 is a competitive inhibitor that binds with high selectivity to the coenzyme Q-binding pocket in SQOR. STI1 exhibits very low cytotoxicity and attenuats the hypertrophic response of neonatal rat ventricular cardiomyocytes and H9c2 cells induced by neurohormonal stressors
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additional information
inhibitor identification by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. The coenzyme Q-binding pocket in human SQOR is a druggable target. Discovery of over 500 compounds that inhibit SQOR with IC50 below 0.02 mM, and discovery of a potent series (class A/A') of SQOR inhibitors, which block substrate access to the CoQ-binding site leading to competitive inhibition
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additional information
inhibitor identification by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. The coenzyme Q-binding pocket in human SQOR is a druggable target. Discovery of over 500 compounds that inhibit SQOR with IC50 below 0.02 mM, and discovery of a potent series (class A/A') of SQOR inhibitors, which block substrate access to the CoQ-binding site leading to competitive inhibition
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additional information
inhibitor identification by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. STI1 is able to inhibit hypertrophic growth of neonatal rat ventricular cardiomyocytes (NRVMs) and H9c2 cells induced by various agonists, e.g. angiotensin II
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
Michaelis-Menten analysis of SQR activity at varying CoA concentrations. Pre-steady state kinetic analysis of ndSQR-mediated sulfur transfer to CoA
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additional information
additional information
substrate promiscuity and comparative kinetic analysis
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000048
2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile
pH and temperature not specified in the publication
-
0.0000115
2-methoxy-4-phenyl-5H-indeno[1,2-b]pyridine-3-carbonitrile
pH and temperature not specified in the publication
-
0.000174
4-(2-chlorophenyl)-2-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile
pH and temperature not specified in the publication
-
0.0000144
4-(4-aminophenyl)-6-methoxy-3'-methyl[2,2'-bipyridine]-5-carbonitrile
pH and temperature not specified in the publication
-
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000094
2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile
Homo sapiens
pH and temperature not specified in the publication
-
0.000021
2-methoxy-4-phenyl-5H-indeno[1,2-b]pyridine-3-carbonitrile
Homo sapiens
pH and temperature not specified in the publication
-
0.00034
4-(2-chlorophenyl)-2-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile
Homo sapiens
pH and temperature not specified in the publication
-
0.000029
4-(4-aminophenyl)-6-methoxy-3'-methyl[2,2'-bipyridine]-5-carbonitrile
Homo sapiens
pH and temperature not specified in the publication
-
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
mitochondrial inner membrane-anchored enzyme
brenda
integral membrane protein, the two C-terminal helices lie in the plane of the mitochondrial membrane, with their hydrophobic faces communicating with the membrane interior. This monotopic mode of association allows the enzyme to gain access to its hydrophobic electron acceptor, CoQ
brenda
ScSQR is located only in the mitochondria, no signal peptide is found
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
human SQOR belongs to a family of flavoprotein disulfide reductases (FDR), members of which contain a pair of redox-active cysteine residues that typically form a disulfide in the resting enzyme
evolution
SQOR is a member of the diverse and extensive flavin disulfide reductase (FDR) superfamily. Group 4 FDRs, which includes SQOR, are the most diverse both structurally and functionally. SQORs contain two redox active cysteines that are widely separated in the primary sequence but are spatially proximal. A hallmark of this subgroup is that they can utilize diverse substrates. Many members, including SQOR and flavocytochrome c sulfide dehydrogenase (FCSD), do not use pyridine nucleotides, but instead, substitute CoQ (in SQOR), or cytochrome c (in FCSD) as an electron acceptor. In both of these cases, the enzymes oxidize sulfide. SQOR utilizes several of the chemical principles common to the FDR superfamily, as well as some unique sulfurbased chemistry during the catalytic cycle
evolution
sulfide quinone oxidoreductase (SQOR) is a member of the flavin disulfide reductase superfamily
malfunction
cyanolysis leads to reversible loss of SQOR activity that is restored in the presence of sulfide. Inherited deficiency of SQOR presents as Leigh disease. Cyanolysis of the bridging sulfur decreases enzyme SQOR protein stability
malfunction
inherited deficiency of SQOR presents as a cause of Leigh disease with decreased complex IV activity. The symptoms include lactic acidosis, multi-organ failure, neurological disorders, and Leigh-like brain lesions. Two patients who are siblings are homozygous for the Glu213Lys mutation, affecting a residue that is remote from the active site, but predicted to disrupt hydrogen bonding with neighboring arginine residues. The third patient is homozygous for a single base pair deletion (c446delT) in the SQOR gene, predicted to lead to mRNA degradation or production of nonfunctional enzyme due to the resulting frameshift. The mutations lead to greatly diminished SQOR levels in tissues expressing the Glu213Lys mutation while SQOR is not detected in fibroblasts carrying the deletion mutation. Complex IV activity but not its assembly is adversely affected by SQOR deficiency. The gastrointestinal defects and accumulation of acylcarnitines reported for ETHE1 deficiency are not seen in SQOR deficiency although elevated H2S is reported for both conditions
malfunction
STI1 dramatically improves survival, preserves cardiac function, and prevents the progression to HFrEF by impeding the transition from compensated to decompensated left ventricle hypertrophy
malfunction
treatment of transverse aortic constriction (TAC) mice with enzyme SQOR inhibitor STI1 mitigates the development of cardiomegaly, pulmonary congestion, dilatation of the left ventricle, and cardiac fibrosis and decreases the pressure gradient across the aortic constriction. STI1 dramatically improves survival, preserves cardiac function, and prevents the progression to HFrEF by impeding the transition from compensated to decompensated left ventricle hypertrophy
malfunction
treatment of transverse aortic constriction (TAC) mice with enzyme SQOR inhibitor STI1 mitigates the development of cardiomegaly, pulmonary congestion, dilatation of the left ventricle, and cardiac fibrosis and decreases the pressure gradient across the aortic constriction. STI1 mitigates the pressure gradient across the aortic constriction created by TAC
metabolism
hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Heart failure patients with reduced ejection fraction (HFrEF) exhibit low levels of H2S. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling
metabolism
hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling
metabolism
hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling
metabolism
sulfide quinone oxidoreductase (SQOR) catalyzes the first and committing step in the mitochondrial sulfide oxidation pathway, overview. Hydrogen sulfide (H2S) is an environmental toxin and a heritage of ancient microbial metabolism, acting as a neuromodulator. While many physiological responses have been attributed to low H2S levels, higher levels inhibit complex IV in the electron transport chain. To prevent respiratory poisoning, a dedicated set of enzymes that make up the mitochondrial sulfide oxidation pathway exists to clear H2S. The committed step in this pathway is catalyzed by sulfide quinone oxidoreductase (SQOR), which couples sulfide oxidation to coenzyme Q10 reduction in the electron transport chain. The SQOR reaction prevents H2S accumulation and generates highly reactive persulfide species as products. These can be further oxidized or can modify cysteine residues in proteins by persulfidation. Alternatively, sulfite is oxidized to sulfate by sulfite oxidase, which resides in the intermembrane space. Electrons from the sulfide oxidation pathway enter the electron transfer chain at the level of Complex III (from SQOR) and cytochrome c/Complex IV (from sulfite oxidase). Interplay of sulfide and butyrate oxidation. The activities of SQOR and ACADS both drive electrons into the mitochondrial Q pool, which restricts the capacity for sulfide oxidation during acute H2S exposure. As a countermeasure, SQOR can catalyze the formation of CoA-SSH, a tightbinding inhibitor of ACADs. Inhibition of ACADS by CoA-SSH relieves competition for the Q pool to prioritize sulfide oxidation. Under certain pathological conditions, such as sulfite oxidase deficiency that is marked by elevated sulfite, oxidative stress conditions that lead to GSH depletion, or periodontitis marked by elevated methanethiol, adventitious nucleophilic additions into the active site trisulfide in SQOR can become physiologically relevant and lead to impaired H2S clearance. Sulfide oxidation by SQOR can exert a direct influence on bioenergetics via the mitochondrial CoQ pool, which represents a major redox nexus. Coupling of SQOR activity to the CoQ pool creates intersections between sulfide metabolism and: 1. complex I, which oxidizes NADH, 2. complex II, which oxidizes succinate and FADH2, 3. dihydroorotate dehydrogenase, which is involved in de novo pyrimidine biosynthesis, 4. glycerol-3-phosphate dehydrogenase, which links to both carbohydrate and lipid metabolism, and 5. the electron-transferring flavoprotein dehydrogenase, which is involved in fatty acid and branched chain amino acid metabolism. Acute exposure to high H2S levels in the colon, with a consequent decrease in the CoQ/CoQH2 ratio could limit other activities that rely on an oxidized CoQ pool. Thus, in addition to respiratory inhibition, H2S oxidation can also inhibit other oxidative metabolic pathways
metabolism
sulfide quinone oxidoreductase (SQOR) catalyzes the first step in sulfide clearance, coupling H2S oxidation to coenzyme Q reduction
metabolism
sulfide:quinone oxidoreductase (SQOR) catalyzes the first irreversible step in the mitochondrial metabolism of hydrogen sulfide (H2S). SQOR plays a major role in controlling physiological levels of H2S and sits at a key pharmacological intervention point
physiological function
due to the little exchange of seawater and to anoxic conditions, Sinonovacula constricta is exposed to considerable amounts of sulfide during low tide, but exhibits strong sulfide tolerance. Mitochondrial sulfide oxidation is a particular defense strategy against sulfide toxicity of sulfide-tolerant organisms, for which sulfide:quinone oxidoreductase (SQR) is the first key enzyme. In order to investigate the mechanism of sulfide tolerance including ScSQR. Th enzyme has an important role in protecting cells from sulfide stress by participating in mitochondrial sulfide detoxification, it catalyzes electron transfer from sulfide to ubiquinone through the FAD cofactor
physiological function
higher H2S levels inhibit complex IV in the electron transport chain. To prevent respiratory poisoning, a dedicated set of enzymes that make up the mitochondrial sulfide oxidation pathway exists to clear H2S. The committed step in this pathway is catalyzed by sulfide quinone oxidoreductase (SQOR), which couples sulfide oxidation to coenzyme Q10 reduction in the electron transport chain. The SQOR reaction prevents H2S accumulation and generates highly reactive persulfide species as products. These can be further oxidized or can modify cysteine residues in proteins by persulfidation. The human SQOR shows unconventional redox cofactor configuration and substrate promiscuity leading to sulfide clearance and potentially expand the signaling potential of H2S. SQOR is a mitochondrial inner membrane-anchored flavoenzyme that is poised to play a critical role in H2S-based signaling while also serving as a guardian of the electron transfer chain against H2S poisoning. Interplay of sulfide and butyrate oxidation. The activities of SQOR and ACADS both drive electrons into the mitochondrial Q pool, which restricts the capacity for sulfide oxidation during acute H2S exposure. As a countermeasure, SQOR can catalyze the formation of CoA-SSH, a tightbinding inhibitor of ACADs. Inhibition of ACADS by CoA-SSH relieves competition for the Q pool to prioritize sulfide oxidation. The promiscuity of SQOR can be traced to the large electropositive entrance to the active site that accommodates a range of substrates and has the potential to generate a variety of low-molecular-weight persulfides. The production of CoA-SSH, long known as a tight binding inhibitor of ACADS, has been traced to the relaxed substrate specificity of SQOR and can prioritize sulfide over butyrate oxidation during acute colonic exposure to H2S. It is yet not known whether other persulfides are produced via SQOR in a tissue-specific manner and in response to intra- or extracellular triggers. SQOR was proposed to play a role in proteostasis overview
physiological function
hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Heart failure patients with reduced ejection fraction (HFrEF) exhibit low levels of H2S. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling
physiological function
hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling
physiological function
hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling
physiological function
hydrogen sulfide (H2S) is a signaling molecule that exerts physiological effects in the cardiovascular, central nervous, and gastrointestinal systems. At higher concentrations, H2S can act as a respiratory poison that blocks the electron transport chain by inhibiting complex IV. Due to the dual effects of H2S, its levels must be strictly regulated. The accumulation of toxic concentrations of H2S is prevented by its oxidation to thiosulfate and sulfate via the mitochondrial sulfide oxidation pathway. The first and committed step in this pathway is catalyzed by sulfide quinone oxidoreductase (SQOR), an inner mitochondrial membrane-anchored flavoprotein. SQOR catalyzes coupling of H2S oxidation to coenzyme Q reduction. It transfers the oxidized sulfane sulfur to a small molecule acceptor, which is predicted to be glutathione (GSH) under physiological conditions
physiological function
SQOR plays a major role in controlling physiological levels of H2S. SQOR catalyzes a two-electron oxidation of H2S to sulfane sulfur (S0). It uses coenzyme Q (CoQ) as electron acceptor and sulfite or glutathione as sulfane sulfur acceptor in reactions that produce thiosulfate or glutathione persulfide (GSS-), respectively
physiological function
the catalytic promiscuity of human sulfide quinone oxidoreductase supports formation of CoA-persulfide, a known inhibitor of short-chain fatty acid oxidation in colonocytes, analysis of several enzyme crystal structures shows a different mechanism for sulfide oxidation, which is catalyzed by an active site cysteine trisulfide. Identification of CoA as an additional sulfur acceptor for human SQR, its generation in situ leads to formation of the inhibitory CoA-SS- to FAD charge-transfer complex in human ACADS (short-chain specific acyl-CoA dehydrogenase)
additional information
molecular basis for the enzyme's ability to catalyze sulfane sulfur transfer reactions with structurally diverse acceptors, molecular basis for the enzyme's ability to catalyze sulfane sulfur transfer reactions with structurally diverse acceptors, overview. Human SQOR contains unique features: an electro-positive surface depression implicated as a binding site for sulfane sulfur acceptors and postulated to funnel negatively charged substrates to a hydrophilic H2S-oxidizing active site, which is connected to a hydrophobic internal tunnel that binds coenzyme Q. The enzyme has a unique binding site for sulfane sulfur acceptors. The two active-site cysteine residues (Cys201, Cys379) lie just above the re-face of the flavin ring. In both the SeMet-substituted and native enzyme structures, these cysteine residues are linked by a bridging sulfur to form thiocystine (Cys-S-S-S-Cys). Structure-analysis relationship, overview. The two C-terminal helices lie in the plane of the mitochondrial membrane, with their hydrophobic faces communicating with the membrane interior. This monotopic mode of association allows the enzyme to gain access to its hydrophobic electron acceptor, CoQ. The position of the C-terminal helix is likely perturbed by a crystal contact with the penultimate helix in a symmetry-related molecule. Thus, the last residue in the C-terminal helix, Glu452, forms hydrogen bonds with residues (Arg411, Leu412, Ser413) in the penultimate helix of the adjacent chain
additional information
structural basis for catalytic promiscuity in SQOR, overview. Electrostatic surface potential map of the SQOR monomer, revealing a large electropositive cavity containing the exposed 379Cys-SSH persulfide. GSH is docked in the cavity, binding structure analysis
additional information
structures of human SQOR reveal a sulfur atom bridging the SQOR active site cysteines in a trisulfide configuration. Computational modeling and molecular dynamics simulations revealed an about 105fold rate enhancement for nucleophilic addition of sulfide into the trisulfide versus a disulfide cofactor. The cysteine trisulfide in SQOR is thus critical for activity and provides a significant catalytic advantage over a cysteine disulfide. Descriptors of intrinsic reactivity derived from the electronic structure of Cys379 and Cys201 are calculated at the QM/MM level in the framework of a conceptual DFT. DFT-PCM modeling of reaction mechanisms and barriers for sulfide nucleophilic attack, detailed overview
additional information
the deduced ScSQR protein contains conserved FAD-binding domains, two cysteine residues (C190 and C371), two histidines (H68 and H282), and one glutamic acid (E147), which are the essential elements for the catalytic mechanism of SQR
additional information
-
the deduced ScSQR protein contains conserved FAD-binding domains, two cysteine residues (C190 and C371), two histidines (H68 and H282), and one glutamic acid (E147), which are the essential elements for the catalytic mechanism of SQR
additional information
the large cavity extending from the matrix face to the active site exposes Cys379 and explains the vulnerability of solubilized SQR to errant attack by nucleophiles (sulfite, GSH, homocysteine, cysteine and methanethiol). Docking models reveal that either GSH or CoA can be accommodated at the mouth of the cavity with their thiol moieties oriented to interact with the 379Cys-SSH intermediate. The significantly greater intracellular concentration of GSH than sulfite or methanethiol, except perhaps under pathological conditions, is predicted to favor GSSH formation. Overall structure and active site architecture of SQR, overview. The sulfur substrate entry site is on the matrix side, CoQ entry from the mitochondrial membrane side
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SQOR_DICDI
452
0
50145
Swiss-Prot
Secretory Pathway (Reliability: 4)
SQOR_HUMAN
450
0
49961
Swiss-Prot
Mitochondrion (Reliability: 2)
SQOR_MOUSE
450
0
50282
Swiss-Prot
Mitochondrion (Reliability: 1)
A0A8J8WAE0_9EURO
452
0
48634
TrEMBL
Mitochondrion (Reliability: 1)
A0A6J8D7K5_MYTCO
429
0
47696
TrEMBL
Mitochondrion (Reliability: 2)
A0A812D402_SEPPH
421
0
46979
TrEMBL
other Location (Reliability: 3)
A0A6J8D2X2_MYTCO
450
0
50009
TrEMBL
other Location (Reliability: 5)
B0LD08_AREMA
458
0
50991
TrEMBL
other Location (Reliability: 4)
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
human SQOR comprises two tandem Rossmann fold domains and a C-terminal domain containing two helices (denoted the C-terminal and penultimate C-terminal helices). FAD is noncovalently bound in an extended conformation and is in the oxidized state. The first Rossmann fold starts near the N-terminus and binds the ADP portion of FAD. The second Rossmann fold is closer to the isoalloxazine ring of FAD but is mostly positioned at least 10 A away from the flavin ring with one notable exception. SQOR quaternary structure, detailed overview
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
glycoprotein
three putative glycosylation sites (NNTV, NISY, NTSL) are predicted
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified selenomethionine-substituted and native enzyme, X-ray diffraction structure determination analysis at 2.59 and 2.99 A resolution, respectively, the SeMet and native structures are essentially identical
purified SQOR-CoQ1 complexed with cyanide, hanging drop vapor diffusion method, mixing of 17.4 mg/ml solubilized human SQOR in 50 mM Tris-HCl, pH 8.0, 300 mM NaCl, 0.05% w/v n-dodecyl beta-D-maltoside, and 5 mM CoQ1 (in 100% DMSO), with reservoir solution composed of 200 mM ammonium tartrate dibasic, pH 6.6, and 20% w/v PEG 3350, yielding a final CoQ1 concentration of 2.5 mM, in a 1:1 ratio, at 20°C, soaking of crystals with 10 mM potassium cyanide solution for 45 min, X-ray diffraction structure determination analysis at 2.25 A resolution, molecular replacement using a SQOR-CoQ1 structure (PDB ID 6OIB) as a search model, structure modeling
purified SQR in the absence and presence of CoQ1, a soluble CoQ10 analogue, and with/without sulfite or sulfide, X-ray diffraction structure determination and analysis at 2.0-2.8 A resolution. Soaking SQR-CoQ1 crystals with sodium sulfide provided evidence for in crystallo catalysis and captures CoQ1 exiting a long hydrophobic channel leading from FAD to the putative membrane-facing surface of SQR
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E213K
naturally occuring mutation the mutation affects a residue that is remote from the active site, but predicted to disrupt hydrogen bonding with neighboring arginine residues. The mutation leads to greatly diminished SQOR levels in tissues expressing the E213K mutation
additional information
a patient is homozygous for a single base pair deletion (c446delT) in the SQOR gene, predicted to lead to mRNA degradation or production of nonfunctional enzyme due to the resulting frameshift, SQOR is not detected in fibroblasts carrying the deletion mutation
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
cyanolysis of the bridging sulfur decreases enzyme SQOR protein stability
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
nickel chelate resin column chromatography and DEAE-Sephadex gel filtration
-
recombinant His-tagged enzyme from Escherichia coli strain BL21 by nickel affinity chromatography from inclusion bodies. Native enzyme partially from gills by purification of mitochondria
Resource Q column chromatography, Source S column chromatography, and Superdex 75 gel filtration
Resource Q column chromatography, Source S column chromatography, and Superdex 75 gel filtration
-
Resource Q column chromatography, Source S column chromatography, and Superdex 75 gel filtration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21(DE3) cells
gene sqr, DNA and amino acid sequence determination and analysis, sequence comparisons, quantitative real-time RT-PCR expression analysis, recombinant expression of N- and C-terminally His-tagged enzyme in Escherichia coli strain BL21 in inclusion bodies
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
enzyme expression increases significantly at 12 h in 0.05 mM sulfide and 6 h in 0.15 mM sulfide and then continues to increase with time
enzyme expression is induced by 0.15 mM sulfide. In the gill, the expression level of ScSQR increases significantly and shows a time-dependent pattern. In addition, under sulfide stress, the expression level of the gill is higher than that of liver, overview
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
drug development
the coenzyme Q-binding pocket in human SQOR is a druggable target, potential of SQOR inhibitors to provide a therapeutic approach for the treatment of heart failure patients with reduced ejection fraction (HFrEF)
drug development
the coenzyme Q-binding pocket in human SQOR is a druggable target, potential of SQOR inhibitors to provide a therapeutic approach for the treatment of heart failure patients with reduced ejection fraction (HFrEF)
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Landry, A.; Ballou, D.; Banerjee, R.
H2S oxidation by nanodisc-embedded human sulfide quinone oxidoreductase
J. Biol. Chem.
292
11641-11649
2017
Homo sapiens (Q9Y6N5)
brenda
Jackson, M.R.; Melideo, S.L.; Jorns, M.S.
Role of human sulfide quinone oxidoreductase in H2S metabolism
Methods Enzymol.
554
255-270
2015
Homo sapiens (Q9Y6N5)
brenda
Jackson, M.; Melideo, S.; Jorns, M.
Human sulfide quinone oxidoreductase catalyzes the first step in hydrogen sulfide metabolism and produces a sulfane sulfur metabolite
Biochemistry
51
6804-6815
2012
Homo sapiens (Q9Y6N5)
-
brenda
Augustyn, K.; Jackson, M.; Jorns, M.
Use of tissue metabolite analysis and enzyme kinetics to discriminate between alternate pathways for hydrogen sulfide metabolism
Biochemistry
56
986-996
2017
Homo sapiens (Q9Y6N5)
brenda
Hildebrandt, T.; Grieshaber, M.
Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria
FEBS J.
275
3352-3361
2008
Rattus norvegicus, Arenicola marina (B0LD08)
brenda
Vande Weghe, J.; Ow, D.
A fission yeast gene for mitochondrial sulfide oxidation
J. Biol. Chem.
274
13250-13257
1999
Schizosaccharomyces pombe, Schizosaccharomyces pombe JS23
brenda
Libiad, M.; Yadav, P.; Vitvitsky, V.; Martinov, M.; Banerjee, R.
Organization of the human mitochondrial hydrogen sulfide oxidation pathway
J. Biol. Chem.
289
30901-30910
2014
Homo sapiens (Q9Y6N5)
brenda
Ma, Y.; Zhang, Z.; Shao, M.; Kang, K.; Tan, Z.; Li, J.
Sulfide quinone oxidoreductase from echiuran worm Urechis unicinctus
Mar. Biotechnol.
13
93-107
2011
Urechis unicinctus (H2KXA2)
brenda
Ma, Y.; Zhang, Z.; Shao, M.; Kang, K.; Shi, X.; Dong, Y.; Li, J.
Response of sulfide quinone oxidoreductase to sulfide exposure in the echiuran worm Urechis unicinctus
Mar. Biotechnol.
14
245-251
2012
Urechis unicinctus (H2KXA2)
brenda
Jackson, M.R.; Cox, K.D.; Baugh, S.D.P.; Wakeen, L.; Rashad, A.A.; Lam, P.Y.S.; Polyak, B.; Jorns, M.S.
Discovery of a first-in-class inhibitor of sulfide quinone oxidoreductase that protects against adverse cardiac remodeling and heart failure
Cardiovasc. Res.
118
1771-1784
2022
Rattus norvegicus (B0BMT9), Mus musculus (Q9R112), Homo sapiens (Q9Y6N5)
brenda
Landry, A.P.; Moon, S.; Kim, H.; Yadav, P.K.; Guha, A.; Cho, U.S.; Banerjee, R.
A catalytic trisulfide in human sulfide quinone oxidoreductase catalyzes coenzyme A persulfide synthesis and inhibits butyrate oxidation
Cell Chem. Biol.
26
1515-1525.e4
2019
Homo sapiens (Q9Y6N5)
brenda
Landry, A.P.; Ballou, D.P.; Banerjee, R.
Hydrogen sulfide oxidation by sulfide quinone oxidoreductase
ChemBioChem
22
949-960
2021
Homo sapiens (Q9Y6N5)
brenda
Shen, Y.; Chen, J.; Shen, W.; Chen, C.; Lin, Z.; Li, C.
Molecular characterization of a novel sulfide quinone oxidoreductase from the razor clam Sinonovacula constricta and its expression response to sulfide stress
Comp. Biochem. Physiol. B
239
110367
2020
Sinonovacula constricta (A0A6B9CM12), Sinonovacula constricta
brenda
Landry, A.P.; Moon, S.; Bonanata, J.; Cho, U.S.; Coitino, E.L.; Banerjee, R.
Dismantling and rebuilding the trisulfide cofactor demonstrates its essential role in human sulfide quinone oxidoreductase
J. Am. Chem. Soc.
142
14295-14306
2020
Homo sapiens (Q9Y6N5)
brenda
Jackson, M.R.; Loll, P.J.; Jorns, M.S.
X-ray structure of human sulfide quinone oxidoreductase insights into the mechanism of mitochondrial hydrogen sulfide oxidation
Structure
27
794-805.e4
2019
Homo sapiens (Q9Y6N5)
brenda
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