The product is the cyclic imine of the 2-oxoacid corresponding to S-(2-aminoethyl)cysteine. In the reverse direction, a number of other cyclic unsaturated compounds can act as substrates, but more slowly.
in silico docking of various ligands into the active site of the X-ray structure of the enzyme suggests an unusual catalytic mechanism involving an arginine residue as a proton donor
in silico docking of various ligands into the active site of the X-ray structure of the enzyme suggests an unusual catalytic mechanism involving an arginine residue as a proton donor
in silico docking of various ligands into the active site of the X-ray structure of the enzyme suggests an unusual catalytic mechanism involving an arginine residue as a proton donor, proposed mechanism for the reaction catalyzed by ketimine reductase/CRYM, overview
the enzyme binds 2-oxo acids, such as pyruvate, in solution, and catalyzes the formation of N-alkyl-amino acids from alkylamines and 2-oxo acids via reduction of imine intermediates. Mechanistically, ketimine reductase/CRYM acts as a classical imine reductase
The product is the cyclic imine of the 2-oxoacid corresponding to S-(2-aminoethyl)cysteine. In the reverse direction, a number of other cyclic unsaturated compounds can act as substrates, but more slowly.
the non-sulfur substrates exist in equilibrium with open chain forms at low acidic pH. At neutral pH, they exist predominantly as the enzymatically favorable cyclic ketimine form (in which the ring double bond is in the C=N form), while sulfur-containing cyclic ketimine substrates exist predominantly as the enzymatically unfavorable enamine form (in which the ring double bond is in the C=C form) at neutral pH
the non-sulfur substrates exist in equilibrium with open chain forms at low acidic pH. At neutral pH, they exist predominantly as the enzymatically favorable cyclic ketimine form (in which the ring double bond is in the C=N form), while sulfur-containing cyclic ketimine substrates exist predominantly as the enzymatically unfavorable enamine form (in which the ring double bond is in the C=C form) at neutral pH
human ketimine reductase/CRYM can utilize alkylamines (such as methylamine and ethylamine) and 2-oxo acids (such as pyruvate and phenylpyruvate) as enzyme substrates. Analysis of reaction intermediates, overview. Mammalian ketimine reductase reaction is known to be enantiospecific and only the L-enantiomer product is formed in vivo. A ketimine reductase/CRYM-catalyzed reaction at neutral pH in the reverse direction is not determined
the non-sulfur substrates exist in equilibrium with openchain forms at low acidic pH. At neutral pH, they exist predominantly as the enzymatically favorable cyclic ketimine form (in which the ring double bond is in the C=N form), while sulfur-containing cyclic ketimine substrates exist predominantly as the enzymatically unfavorable enamine form (in which the ring double bond is in the C=C form) at neutral pH
the non-sulfur substrates exist in equilibrium with open chain forms at low acidic pH. At neutral pH, they exist predominantly as the enzymatically favorable cyclic ketimine form (in which the ring double bond is in the C=N form), while sulfur-containing cyclic ketimine substrates exist predominantly as the enzymatically unfavorable enamine form (in which the ring double bond is in the C=C form) at neutral pH
the non-sulfur substrates exist in equilibrium with open chain forms at low acidic pH. At neutral pH, they exist predominantly as the enzymatically favorable cyclic ketimine form (in which the ring double bond is in the C=N form), while sulfur-containing cyclic ketimine substrates exist predominantly as the enzymatically unfavorable enamine form (in which the ring double bond is in the C=C form) at neutral pH
the non-sulfur substrates exist in equilibrium with openchain forms at low acidic pH. At neutral pH, they exist predominantly as the enzymatically favorable cyclic ketimine form (in which the ring double bond is in the C=N form), while sulfur-containing cyclic ketimine substrates exist predominantly as the enzymatically unfavorable enamine form (in which the ring double bond is in the C=C form) at neutral pH
reduction rate for cystathionine ketimine, lanthionine ketimine and DELTA1-piperidine 2-carboxylate is higher with NADPH than with NADH. Reduction rate for S-aminoethylcysteine with NADH is higher than with NADPH
NADH and NADPH show equal activity with cystathionine ketimine as substrate. Reduction of lanthionine ketimine with NADPH is faster than reduction with NADH. Reduction of S-aminoethylcysteine with NADH is faster than reduction with NADPH
reduction rate for cystathionine ketimine, lanthionine ketimine and DELTA1-piperidine 2-carboxylate is higher with NADPH than with NADH. Reduction rate for S-aminoethylcysteine with NADH is higher than with NADPH
NADH and NADPH show equal activity with cystathionine ketimine as substrate. Reduction of lanthionine ketimine with NADPH is faster than reduction with NADH. Reduction of S-aminoethylcysteine with NADH is faster than reduction with NADPH
competitive inhibition, picolinate is a much poorer inhibitor than pyrrole-2-carboxylate because it does not possess a ring -NH and relies on a relatively weak ring interaction
competitive inhibition, pyrrole-2-carboxylate is an effective inhibitor of ketimine reductase/CRYM mainly as a result of the -NH hydrogen bonding to an active site residue
high enzyme expression level, expression of the CRYM transcript follows the hair growth cycle with a significant increase in expression during mid- and late anagen growth phases
levels of thyroid hormone binding capacity for cytosolic NADPH-dependent T3 binding are noticeably lower in the cerebellum than in the cerebrum of adult rat brain at all stages of development. NADPH-dependent T3 binding is only detected in kidney, liver, heart and spleen after birth, increasing over the next 6 weeks. NADPH-dependent T3 binding is detected in cerebrum and cerebellum 5 days before birth, increasing with a sharp transient spike at the time of birth, that is specific for the brain, particularly in cerebrum, and cannot be seen in other tissues. The NADPH-dependent T3 binding in cerebrum decreases after birth, but begins to increase again 2 weeks after birth. The level in cerebellum does not show this increase. The brain may contain at least two distinct P2C reductases/ketimine reductase, one of which is predominant in the fore-brain and another that is prominent in the cerebellum
in silico docking of various substrates and small inhibitors into the active site of the X-ray structures of mouse ketimine reductase/CRYM in order to better understand the enzyme catalytic mechanism
Significance of CRYM/KR in psychiatric and neurological disease, overview. Two known point mutations of human CRYM, both of which are associated with nonsyndromic deafness
lysine is catabolized in mammalian tissues by two main pathways: the saccharopine pathway and the pipecolate pathway. The pipecolate pathway is the main route for lysine catabolism in the adult brain, whereas the saccharopine pathway predominates in extracerebral tissues. Iimportance of the pipecolate pathway in brain metabolism. Lysine/ornithine catabolism and interconnected pathways in mammalian tissues, and metabolic pathways involving sulfur-containing cyclic ketimines, overview
lysine is catabolized in mammalian tissues by two main pathways: the saccharopine pathway and the pipecolate pathway. The pipecolate pathway is the main route for lysine catabolism in the adult brain, whereas the saccharopine pathway predominates in extracerebral tissues. Importance of the pipecolate pathway in brain metabolism. Lysine/ornithine catabolism and interconnected pathways in mammalian tissues, and metabolic pathways involving sulfur-containing cyclic ketimines, overview
lysine is catabolized in mammalian tissues by two main pathways: the saccharopine pathway and the pipecolate pathway. The pipecolate pathway is the main route for lysine catabolism in the adult brain, whereas the saccharopine pathway predominates in extracerebral tissues. Importance of the pipecolate pathway in brain metabolism. Lysine/ornithine catabolism and interconnected pathways in mammalian tissues, and metabolic pathways involving sulfur-containing cyclic ketimines, overview
mammalian thyroid hormone-binding protein CRYM has an additional biological role as a ketimine reductase, CRYM is a P2C reductase. CRYM shows an extremely strong affinity for 3,5,3'-triiodothyronine T3 in the presence of NADPH. The enzyme seems to be tightly regulated in vivo by 3,5,3'-triiodothyronine (T3) at low concentrations, T3 bioavailability is likely strongly dependent on the pipecolate pathway activity
mammalian thyroid hormone-binding protein CRYM has an additional biological role as a ketimine reductase, CRYM is a P2C reductase. CRYM shows an extremely strong affinity for 3,5,3'-triiodothyronine T3 in the presence of NADPH. The enzyme seems to be tightly regulated in vivo by 3,5,3'-triiodothyronine (T3) at low concentrations, T3 bioavailability is likely strongly dependent on the pipecolate pathway activity
mammalian thyroid hormone-binding protein CRYM has an additional biological role as a ketimine reductase, CRYM is a P2C reductase. CRYM shows an extremely strong affinity for 3,5,3'-triiodothyronine T3 in the presence of NADPH. The enzyme seems to be tightly regulated in vivo by 3,5,3'-triiodothyronine (T3) at low concentrations, T3 bioavailability is likely strongly dependent on the pipecolate pathway activity
mammalian thyroid hormone-binding protein CRYM has an additional biological role as a ketimine reductase, CRYM is a P2C reductase. CRYM shows an extremely strong affinity for 3,5,3'-triiodothyronine T3 in the presence of NADPH. The enzyme seems to be tightly regulated in vivo by 3,5,3'-triiodothyronine (T3) at low concentrations, T3 bioavailability is likely strongly dependent on the pipecolate pathway activity. Levels of CRYM/KR substrates are important determinants in hearing as CRYM mRNA is highly expressed in human inner ear
mammalian thyroid hormone-binding protein CRYM has an additional biological role as a ketimine reductase, CRYM is a P2C reductase. CRYM shows an extremely strong affinity for 3,5,3'-triiodothyronine T3 in the presence of NADPH. The enzyme seems to be tightly regulated in vivo by 3,5,3'-triiodothyronine (T3) at low concentrations, T3 bioavailability is likely strongly dependent on the pipecolate pathway activity. Possible involvement of CRYM in the development of mouse hair follicles during the anagen phase. Enzyme substrates (e.g. sulfur-containing cyclic ketimines such as S-(2-aminoethyl)-L-cysteine ketimine) may play a role in regulating cell growth and/or cell differentiation
the enzyme is the main cytosolic thyroid hormone binding protein and shows strong binding to 3,5,3'-triiodothyronine (T3), the active form of thyroxine. Ketimine reductase/CRYM substrate levels and T3 bioavailability are reciprocally linked. Human ketimine reductase/CRYM catalyzes reduction of non-cyclic imines. Since a ketimine reductase/CRYM-catalyzed reaction at neutral pH in the reverse direction cannot be demonstrated, ketimine reductase/CRYM-catalyzed reductive amination/alkylamination of 2-oxo acids (or oxidation of L-amino acids/N-alkyl-L-amino acids) is not likely to be of physiological importance in mammals in vivo
the thyroid hormone-binding protein CRYM has an additional biological role as a ketimine reductase, CRYM is a P2C reductase. CRYM shows an extremely strong affinity for 3,5,3'-triiodothyronine T3 in the presence of NADPH. The enzyme seems to be tightly regulated in vivo by 3,5,3'-triiodothyronine (T3) at low concentrations, T3 bioavailability is likely strongly dependent on the pipecolate pathway activity
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
irreversible inactivation at protein concentration below 1 mg/ml. Complete loss of activity after 24 h at 4°C. Higher protein concentrations or 10% glycerol prevent enzyme inactivation. 30% loss of activity aftter 7 days at 4°C