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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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sulfide : quinone oxidoreductase
sulfide:quinone oxidoreductase
SQOR
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SQR
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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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-
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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
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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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-
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ir
hydrogen sulfide + glutathione + decylubiquinone
S-sulfanylglutathione + decylubiquinol
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-
-
?
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
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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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-
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ir
hydrogen sulfide + glutathione + quinone
S-sulfanylglutathione + quinol
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-
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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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-
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?
hydrogen sulfide + glutathione + quinone
S-sulfanylglutathione + quinol
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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
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2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile
HTS12441
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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
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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