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Literature summary for 1.2.1.12 extracted from

  • Danshina, P.; Qu, W.; Temple, B.; Rojas, R.; Miley, M.; Machius, M.; Betts, L.; OBrien, D.
    Structural analyses to identify selective inhibitors of glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme (2016), Mol. Hum. Reprod., 22, 410-426 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 1.2.1.12

Application

Application Comment Organism
additional information selective inhibition of GAPDHS, one of the glycolytic isozymes with restricted expression during spermatogenesis, is a potential strategy for the development of a non-hormonal contraceptive that directly blocks sperm function. Detailed structural comparisons of sperm-specific glyceraldehyde 3-phosphate dehydrogenase, spermatogenic (GAPDHS) and the somatic glyceraldehyde 3-phosphate dehydrogenase (GAPDH) isozyme can facilitate the identification of selective GAPDHS inhibitors for contraceptive development Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
recombinant enzyme expression Homo sapiens
recombinant enzyme expression of GST-tagged GAPDH in gapA-deficient Escherichia coli strain DS112 Mus musculus
recombinant enzyme expression of GST-tagged tGAPDHS (amino acids 76-408) in gapA-deficient Escherichia coli strain DS112 Homo sapiens
recombinant enzyme expression of MBP-tagged tGAPDHS (amino acids 106-438) in gapA-deficient Escherichia coli strain DS112 Mus musculus

Crystallization (Commentary)

Crystallization (Comment) Organism
analysis of human GAPDH crystal structure, PDB ID 1U8F Homo sapiens
purified recombinant apo-enzyme tGAPDHS, hanging-drop vapor-diffusion method, 10 mg/ml in 10 mM HEPES, pH 7.5, 500 mM NaCl, 5% glycerol, 0.5 mM TCEP, and 0.01% of sodium azide, is mixed in a 1:1 volume ratio with reservoir solution containing 0.2 M Na2SO4, 0.1 M Bis-Tris propane, pH 6.5, and 20% PEG 3350, 20°C, 2 days, crystallization of purified recombinant holoenzyme tGAPDHS in complex with NAD+, hanging-drop vapor-diffusion method, 10 mg/ml in 10 mM HEPES, pH 7.5, 500 mM NaCl, 5% glycerol, 0.5 mM TCEP, and 0.01% of sodium azide, is mixed in a 1:1 volume ratio with reservoir solution 0.2M NaNO3, and 20% PEG3350, 20°C, 2 days, X-ray diffraction structure determination and analysis at a.86 A (apoenzyme) and 1.73 A (holoenzyme) resolutions, method screening Homo sapiens
purified recombinant apo-enzyme tGAPDHS, hanging-drop vapor-diffusion method, 3 mg/ml protein in PBS is mixed in a 1:1 volume ratio with reservoir solution containing 0.2 M potassium thiocyanate, 0.1 M Bis-Tris propane, pH 6.5, and 20% PEG 3350, 20°C, 6 days, X-ray diffraction structure determination and analysis at 2.01 A resolution Mus musculus

Inhibitors

Inhibitors Comment Organism Structure
T0501_7749 2-[2-amino-3-(4-methylphenyl)sulfonylpyrrolo[3,2-b]quinoxalin-1-yl]-1-(4-nitrophenyl)ethanol, a small-molecule, highly selective isozyme GAPDHS inhibitor, molecular docking simulations in GAPDHS and GAPDH isozymes, binding structure, overview; 2-[2-amino-3-(4-methylphenyl)sulfonylpyrrolo[3,2-b]quinoxalin-1-yl]-1-(4-nitrophenyl)ethanol, identification of a small-molecule GAPDHS inhibitor with micromolar potency and high selectivity that exerts the expected inhibitory effects on sperm glycolysis and motility. The compound causes significant reductions in the percentage of motile human sperm. Molecular docking simulations in GAPDHS and GAPDH isozymes, binding structure, overview Homo sapiens
T0501_7749 2-[2-amino-3-(4-methylphenyl)sulfonylpyrrolo[3,2-b]quinoxalin-1-yl]-1-(4-nitrophenyl)ethanol, a small-molecule, highly selective isozyme GAPDHS inhibitor, molecular docking simulations in GAPDHS and GAPDH isozymes, binding structure, overview; 2-[2-amino-3-(4-methylphenyl)sulfonylpyrrolo[3,2-b]quinoxalin-1-yl]-1-(4-nitrophenyl)ethanol, a small-molecule, highly selective isozymeGAPDHS inhibitor, the compound causes significant reductions in mouse sperm lactate production and in the percentage of motile mouse sperm. Molecular docking simulations in GAPDHS and GAPDH isozymes, binding structure, overview Mus musculus
T0506_9350 1-cyclohexyl-3-[4-[(4-methoxyphenyl)sulfamoyl]-2-nitroanilino]urea, a partial selective isozyme GAPDH inhibitor, binding structure, overview; 1-cyclohexyl-3-[4-[(4-methoxyphenyl)sulfamoyl]-2-nitroanilino]urea, a partial selective isozyme GAPDH inhibitor, binding structure, overview. T0506_9350 inhibition of human and mouse tGAPDHS is competitive with both D-glyceraldehyde 3-phosphate and NAD+ Homo sapiens
T0506_9350 1-cyclohexyl-3-[4-[(4-methoxyphenyl)sulfamoyl]-2-nitroanilino]urea, a partial selective isozyme GAPDH inhibitor, binding structure, overview. T0506_9350 inhibition of human and mouse tGAPDHS is competitive with both D-glyceraldehyde 3-phosphate and NAD+ Mus musculus

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
D-glyceraldehyde 3-phosphate + phosphate + NAD+ Homo sapiens
-
 3-phospho-D-glyceroyl phosphate + NADH + H+
-
 ?
D-glyceraldehyde 3-phosphate + phosphate + NAD+ Mus musculus
-
 3-phospho-D-glyceroyl phosphate + NADH + H+
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens O14556
-
-
Homo sapiens P04406
-
-
Mus musculus P16858
-
-
Mus musculus Q64467
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant GST-tagged GAPDH from gapA-deficient Escherichia coli strain DS112 by glutathione affinity chromatography, and on-column cleavage of the GST-tag by bovine thrombin before elution of the enzyme Mus musculus
recombinant GST-tagged tGAPDHS from gapA-deficient Escherichia coli strain DS112 by glutathione affinity chromatography, and on-column cleavage of the GST-tag by bovine thrombin before elution of the enzyme Homo sapiens
recombinant MBP-tagged tGAPDHS from gapA-deficient Escherichia coli strain DS112 by amylose affinity chromatography, followed by cleavage of the MBP-tag by bovine thrombin dialysis, and anion exchange chromatography Mus musculus

Source Tissue

Source Tissue Comment Organism Textmining
commercial preparation purified from erythrocytes Homo sapiens
-
sperm cell sperm-specific glyceraldehyde 3-phosphate dehydrogenase, restricted enzyme expression during spermatogenesis Homo sapiens
-
sperm cell sperm-specific glyceraldehyde 3-phosphate dehydrogenase, restricted enzyme expression during spermatogenesis Mus musculus
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
D-glyceraldehyde 3-phosphate + phosphate + NAD+
-
 Homo sapiens 3-phospho-D-glyceroyl phosphate + NADH + H+
-
 ?
D-glyceraldehyde 3-phosphate + phosphate + NAD+
-
 Mus musculus 3-phospho-D-glyceroyl phosphate + NADH + H+
-
 ?

Synonyms

Synonyms Comment Organism
GAPDH
-
 Homo sapiens
GAPDH
-
 Mus musculus
GAPDHS
-
 Homo sapiens
GAPDHS
-
 Mus musculus
glyceraldehyde 3-phosphate dehydrogenase
-
 Homo sapiens
glyceraldehyde 3-phosphate dehydrogenase
-
 Mus musculus
glyceraldehyde 3-phosphate dehydrogenase-S
-
 Homo sapiens
glyceraldehyde 3-phosphate dehydrogenase-S
-
 Mus musculus
somatic glyceraldehyde 3-phosphate dehydrogenase
-
 Homo sapiens
somatic glyceraldehyde 3-phosphate dehydrogenase
-
 Mus musculus
sperm-specific glyceraldehyde 3-phosphate dehydrogenase
-
 Homo sapiens
sperm-specific glyceraldehyde 3-phosphate dehydrogenase
-
 Mus musculus

Cofactor

Cofactor Comment Organism Structure
NAD+
-
 Homo sapiens
NAD+
-
 Mus musculus

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
additional information
-
 additional information inhibition kinetics Homo sapiens
additional information
-
 additional information inhibition kinetics Mus musculus
0.0569
-
 T0506_9350 versus NAD+, pH and temperature not specified in the publication Mus musculus
0.0602
-
 T0506_9350 versus NAD+, pH and temperature not specified in the publication Homo sapiens
0.0633
-
 T0506_9350 versus D-glyceraldehyde 3-phosphate, pH and temperature not specified in the publication Homo sapiens
0.071
-
 T0506_9350 versus D-glyceraldehyde 3-phosphate, pH and temperature not specified in the publication Mus musculus

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0012
-
 pH and temperature not specified in the publication Homo sapiens T0501_7749
0.0385
-
 pH and temperature not specified in the publication Homo sapiens T0501_7749
0.0958
-
 pH and temperature not specified in the publication Homo sapiens T0506_9350
0.86
-
 pH and temperature not specified in the publication Homo sapiens T0506_9350

General Information

General Information Comment Organism
malfunction GAPDHS inhibitor effects on sperm motility and metabolism, overview Homo sapiens
malfunction GAPDHS inhibitor effects on sperm motility and metabolism, overview Mus musculus
additional information detailed structural comparisons of sperm-specific glyceraldehyde 3-phosphate dehydrogenase, spermatogenic (GAPDHS) and the somatic glyceraldehyde 3-phosphate dehydrogenase (GAPDH) isozyme of mouse and human, homology modeling of human and mouse GAPDH and GAPDHS isozymes, and binding sites for GAP and NAD+, determined by reference to structures PDB 1DC4 and 1DC6 and crystal structure of Palinurus versicolor GAPDH, PDB ID 1CRW, overview Homo sapiens
additional information detailed structural comparisons of sperm-specific glyceraldehyde 3-phosphate dehydrogenase, spermatogenic (GAPDHS) and the somatic glyceraldehyde 3-phosphate dehydrogenase (GAPDH) isozyme of mouse and human, homology modeling of human and mouse GAPDH and GAPDHS isozymes, and binding sites for GAP and NAD+, determined by reference to structures PDB 1DC4 and 1DC6 and crystal structure of Palinurus versicolor GAPDH, PDB ID 1CRW, overview Mus musculus