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Literature summary for 1.5.1.25 extracted from
- Reciprocal control of thyroid binding and the pipecolate pathway in the brain (2017), Neurochem. Res., 42, 217-243 .
Crystallization (Commentary)
| Crystallization (Comment) | Organism |
|---|---|
| CRYM bound with NADPH, X-ray diffraction structure determination and analysis at 2.6 A resolution | Homo sapiens |
| CRYM bound with NADPH, X-ray diffraction structure determination and analysis, the mouse enzyme also has a bound pyruvate | Mus musculus |
General Stability
| General Stability | Organism |
|---|---|
| the purified recombinant enzyme is unstable even in the presence of substrates and requires factors to stabilize it, e.g. 20% glycerol and 1 mM dithiothreitol (DTT) | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 3,3',5'-L-triiodothyronine | - |
Homo sapiens |  |
| 3,5,3'-L-triiodothyronine | - |
Homo sapiens | |
| 3,5-diiodo-L-tyrosine | - |
Homo sapiens | |
| 3,5-L-diiodothyronine | - |
Homo sapiens | |
| L-thyroxine | - |
Homo sapiens | |
| L-tyrosine | - |
Homo sapiens | |
| additional information | the P2C reductase activity is potently inhibited by thyroid hormones, thyroid hormones and analogues docked into the active site of the crystal structure of human KR, overview | Homo sapiens | |
| additional information | the P2C reductase activity is potently inhibited by thyroid hormones | Mus musculus |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytosol | - |
Mus musculus | 5829 | - |
| cytosol | - |
Homo sapiens | 5829 | - |
| peroxisome | - |
Mus musculus | 5777 | - |
| peroxisome | - |
Homo sapiens | 5777 | - |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| aminoethyl cysteine ketimine + NADPH + H+ | Homo sapiens | - |
thiomorpholine-3-carboxylate | - |
? | |
| lanthionine ketimine + NADPH + H+ | Homo sapiens | - |
thiomorpholine-3,5-dicarboxylate | - |
? | |
| additional information | Mus musculus | reciprocal relationship between thyroid hormone binding and DELTA1-piperideine-2-carboxylate (P2C) binding to ketimine reductase | ? | - |
- |
|
| additional information | Homo sapiens | reciprocal relationship between thyroid hormone binding and DELTA1-piperideine-2-carboxylate (P2C) binding to ketimine reductase | ? | - |
- |
|
| thiomorpholine 3-carboxylate + NAD(P)+ | Mus musculus | - |
3,4-dehydro-thiomorpholine-3-carboxylate + NAD(P)H + H+ | - |
? | |
| thiomorpholine 3-carboxylate + NAD(P)+ | Homo sapiens | - |
3,4-dehydro-thiomorpholine-3-carboxylate + NAD(P)H + H+ | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | Q14894 | - |
- |
| Mus musculus | O54983 | - |
- |
Reaction
| Reaction | Comment | Organism | Reaction ID |
|---|---|---|---|
| thiomorpholine 3-carboxylate + NAD(P)+ = 3,4-dehydro-thiomorpholine-3-carboxylate + NAD(P)H + H+ | proposed catalytic mechanism of ketimine reductase | Mus musculus | |
| thiomorpholine 3-carboxylate + NAD(P)+ = 3,4-dehydro-thiomorpholine-3-carboxylate + NAD(P)H + H+ | proposed catalytic mechanism of ketimine reductase | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| astrocyte | - |
Mus musculus | - |
| astrocyte | - |
Homo sapiens | - |
| brain | - |
Mus musculus | - |
| brain | - |
Homo sapiens | - |
| neuron | - |
Mus musculus | - |
| neuron | - |
Homo sapiens | - |
Storage Stability
| Storage Stability | Organism |
|---|---|
| stored in 20% glycerol and 1 mM dithiothreitol (DTT) at -80°C, the purified recombinant enzyme is quite stable | Homo sapiens |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| aminoethyl cysteine ketimine + NADPH + H+ | - |
Homo sapiens | thiomorpholine-3-carboxylate | - |
? | |
| lanthionine ketimine + NADPH + H+ | - |
Homo sapiens | thiomorpholine-3,5-dicarboxylate | - |
? | |
| lanthionine ketimine + NADPH + H+ | low activity | Homo sapiens | thiomorpholine-3,5-dicarboxylate | - |
? | |
| additional information | reciprocal relationship between thyroid hormone binding and DELTA1-piperideine-2-carboxylate (P2C) binding to ketimine reductase | Mus musculus | ? | - |
- |
|
| additional information | reciprocal relationship between thyroid hormone binding and DELTA1-piperideine-2-carboxylate (P2C) binding to ketimine reductase | Homo sapiens | ? | - |
- |
|
| additional information | purified recombinant human CRYM possesses substantial KR activity. Ketimine reductase is a typical imine reductase | Mus musculus | ? | - |
- |
|
| additional information | purified recombinant human CRYM possesses substantial KR activity. Ketimine reductase is a typical imine reductase. Substrate specificity of recombinant human ketimine reductase (KR) toward DELTA1-piperideine-2-carboxylate (P2CR) and various noncyclized imine intermediates, overview. N-methyl-L-alanine is produced when human KR is incubated in the presence of methylamine, NADPH and pyruvate. Human KR catalyzes the reductive alkylamination of phenylpyruvate and glyoxylate in the presence of methylamine | Homo sapiens | ? | - |
- |
|
| thiomorpholine 3-carboxylate + NAD(P)+ | - |
Mus musculus | 3,4-dehydro-thiomorpholine-3-carboxylate + NAD(P)H + H+ | - |
? | |
| thiomorpholine 3-carboxylate + NAD(P)+ | - |
Homo sapiens | 3,4-dehydro-thiomorpholine-3-carboxylate + NAD(P)H + H+ | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| homodimer | - |
Mus musculus |
| homodimer | 2 * 33776, sequence calculation | Homo sapiens |
| More | each subunit contains two distinct domains linked by an alpha-helix. The first domain (a dinucleotide binding domain) binds NADPH or NADP+ and is built around a Rossmann fold-like motif. The second domain is the dimerization domain and is responsible for recognition and binding of thyroid hormones | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| CRYM | - |
Mus musculus |
| CRYM | - |
Homo sapiens |
| CtBP | - |
Mus musculus |
| CtBP | - |
Homo sapiens |
| cytosolic thyroid hormone binding protein | - |
Mus musculus |
| cytosolic thyroid hormone binding protein | - |
Homo sapiens |
| DELTA1-piperideine-2-carboxylate reductase | - |
Mus musculus |
| DELTA1-piperideine-2-carboxylate reductase | - |
Homo sapiens |
| ketimine reductase | - |
Mus musculus |
| ketimine reductase | - |
Homo sapiens |
| KR/CRYM/CTBP | - |
Mus musculus |
| KR/CRYM/CTBP | - |
Homo sapiens |
| More | see also EC 1.5.1.1 | Mus musculus |
| More | see also EC 1.5.1.1 | Homo sapiens |
| mu-crystallin | - |
Mus musculus |
| mu-crystallin | - |
Homo sapiens |
| P2C reductase | - |
Mus musculus |
| P2C reductase | - |
Homo sapiens |
| PLP-dependent amino acid gamma-substitution enzyme | - |
Mus musculus |
| PLP-dependent amino acid gamma-substitution enzyme | - |
Homo sapiens |
| PYCR2 | - |
Mus musculus |
| PYCR2 | - |
Homo sapiens |
| Pyr2C reductase | - |
Mus musculus |
| Pyr2C reductase | - |
Homo sapiens |
| THBP | - |
Mus musculus |
| THBP | - |
Homo sapiens |
| thyroid hormone binding protein | - |
Mus musculus |
| thyroid hormone binding protein | - |
Homo sapiens |
Temperature Optimum [°C]
| Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
|---|---|---|---|
| 37 | - |
assay at | Mus musculus |
| 37 | - |
assay at | Homo sapiens |
pH Optimum
| pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|
| 5 | - |
- |
Homo sapiens |
pH Range
| pH Minimum | pH Maximum | Comment | Organism |
|---|---|---|---|
| 5 | 7 | 50% higher reaction rate at pH 5.0 compared to pH 7.0 | Homo sapiens |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| additional information | the enzyme uses NADH and NADPH as reductant about equally well | Mus musculus | |
| additional information | the enzyme uses NADH and NADPH as reductant about equally well | Homo sapiens | |
| NAD+ | - |
Mus musculus | |
| NAD+ | - |
Homo sapiens | |
| NADH | - |
Mus musculus | |
| NADH | - |
Homo sapiens | |
| NADP+ | - |
Mus musculus | |
| NADP+ | - |
Homo sapiens | |
| NADPH | - |
Mus musculus | |
| NADPH | - |
Homo sapiens | |
| pyridoxal 5'-phosphate | - |
Mus musculus | |
| pyridoxal 5'-phosphate | - |
Homo sapiens | |
Ki Value [mM]
| Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 0.0006 | - |
L-thyroxine | pH 7.2, 37°C, recombinant enzyme | Homo sapiens | |
| 0.00075 | - |
3,5,3'-L-triiodothyronine | pH 7.2, 37°C, recombinant enzyme | Homo sapiens | |
| 0.032 | - |
3,5-L-diiodothyronine | pH 7.2, 37°C, recombinant enzyme | Homo sapiens | |
| 0.035 | - |
3,3',5'-L-triiodothyronine | pH 7.2, 37°C, recombinant enzyme | Homo sapiens | |
| 0.313 | - |
3,5-diiodo-L-tyrosine | pH 7.2, 37°C, recombinant enzyme | Homo sapiens | |
| 0.8 | - |
L-tyrosine | pH 7.2, 37°C, recombinant enzyme | Homo sapiens | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | enzymes that reduce DELTA1-pyrroline-5-carboxylate and DELTA1-piperideine-6-carboxylate are aldimine reductases whereas enzymes that reduce DELTA1-piperideine-2-carboxylate and DELTA1-pyrroline-2-carboxylate (P2C/Pyr2C) are ketimine reductases (KRs) | Mus musculus |
| evolution | enzymes that reduce DELTA1-pyrroline-5-carboxylate and DELTA1-piperideine-6-carboxylate are aldimine reductases whereas enzymes that reduce DELTA1-piperideine-2-carboxylate and DELTA1-pyrroline-2-carboxylate (P2C/Pyr2C) are ketimine reductases (KRs) | Homo sapiens |
| metabolism | lysine degradation may be divided into two distinct pathways, namely (1) the pipecolate pathway which involves oxidation at the alpha-amino position followed by reduction of the product (P2C) to pipecolate by ketimine reductase (KR), and (2) the saccharopine pathway which involves oxidation at the epsilon-amino position The saccharopine pathway is predominantly mitochondrial, whereas the pipecolate pathway is predominantly cytosolic (but with a portion occurring in the peroxisomes). The DELTA1-piperideine-2-carboxylate (P2C) reductase enzyme activity is potently inhibited by thyroid hormones, thus suggesting a reciprocal relationship between enzyme catalysis and thyroid hormone bioavailability. KR is involved in a number of amino acid metabolic pathways. As DELTA1-piperideine-2-carboxylate (P2C) reductase it plays a role in the pipecolate pathway of lysine metabolism. Potent regulation of KR activity by thyroid hormones. KR is also involved in L-ornithine/L-glutamate/L-proline metabolism as well as sulfur-containing amino acid metabolism. Unique presence of the pipecolate pathway in brain. Cerebral pipecolate pathway, overview | Mus musculus |
| metabolism | lysine degradation may be divided into two distinct pathways, namely (1) the pipecolate pathway which involves oxidation at the alpha-amino position followed by reduction of the product (P2C) to pipecolate by ketimine reductase (KR), and (2) the saccharopine pathway which involves oxidation at the epsilon-amino position The saccharopine pathway is predominantly mitochondrial, whereas the pipecolate pathway is predominantly cytosolic (but with a portion occurring in the peroxisomes). The DELTA1-piperideine-2-carboxylate (P2C) reductase enzyme activity is potently inhibited by thyroid hormones, thus suggesting a reciprocal relationship between enzyme catalysis and thyroid hormone bioavailability. KR is involved in a number of amino acid metabolic pathways. As DELTA1-piperideine-2-carboxylate (P2C) reductase it plays a role in the pipecolate pathway of lysine metabolism. Potent regulation of KR activity by thyroid hormones. KR is also involved in L-ornithine/L-glutamate/L-proline metabolism as well as sulfur-containing amino acid metabolism. Unique presence of the pipecolate pathway in brain. Cerebral pipecolate pathway, overview | Homo sapiens |
| physiological function | identification of ketimine reductase (KR) as mu-crystalin (CRYM)/cytosolic thyroid hormone binding protein (THBP). CRYM is a major mammalian THBP, which has the ability to strongly bind thyroid hormones in an NADPH-dependent fashion. It is also active as a DELTA1-piperideine-2-carboxylate (P2C) reductase, which catalyzes the NAD(P)H-dependent reduction of -C=N- (imine) double bonds of a number of cyclic ketimine substrates including sulfur-containing cyclic ketimines. P2C exists in equilibrium with its open-chain form under acidic conditions, but at neutral pH, P2C exists predominantly as the enzymatically favorable cyclic ketimine form (in which the ring double bond is in the C=N form). P2C can also exist as an enamine, but only at basic pH values. The enzyme activity is potently inhibited by thyroid hormones, thus suggesting a reciprocal relationship between enzyme catalysis and thyroid hormone bioavailability. KR is involved in a number of amino acid metabolic pathways. As DELTA1-piperideine-2-carboxylate (P2C) reductase it plays a role in the pipecolate pathway of lysine metabolism. Potent regulation of KR activity by thyroid hormones. KR is also involved in L-ornithine/L-glutamate/L-proline metabolism as well as sulfur-containing amino acid metabolism. Although KR is important in the formation of L-pipecolate in the brain, it is also an important source of L-proline. This proline (via proline oxidase) in turn is an important source of DELTA1-pyrroline-5-carboxylate (Pyr5C) and hence of glutamate and to a lesser extent ornithine. Ketimine reductase is involved in several diseases | Mus musculus |
| physiological function | identification of ketimine reductase (KR) as mu-crystalin (CRYM)/cytosolic thyroid hormone binding protein (THBP). CRYM is a major mammalian THBP, which has the ability to strongly bind thyroid hormones in an NADPH-dependent fashion. It is also active as a DELTA1-piperideine-2-carboxylate (P2C) reductase, which catalyzes the NAD(P)H-dependent reduction of -C=N- (imine) double bonds of a number of cyclic ketimine substrates including sulfur-containing cyclic ketimines. P2C exists in equilibrium with its open-chain form under acidic conditions, but at neutral pH, P2C exists predominantly as the enzymatically favorable cyclic ketimine form (in which the ring double bond is in the C=N form). P2C can also exist as an enamine, but only at basic pH values. The enzyme activity is potently inhibited by thyroid hormones, thus suggesting a reciprocal relationship between enzyme catalysis and thyroid hormone bioavailability. KR is involved in a number of amino acid metabolic pathways. As DELTA1-piperideine-2-carboxylate (P2C) reductase it plays a role in the pipecolate pathway of lysine metabolism. Potent regulation of KR activity by thyroid hormones. KR is also involved in L-ornithine/L-glutamate/L-proline metabolism as well as sulfur-containing amino acid metabolism. Although KR is important in the formation of L-pipecolate in the brain, it is also an important source of L-proline. This proline (via proline oxidase) in turn is an important source of DELTA1-pyrroline-5-carboxylate (Pyr5C) and hence of glutamate and to a lesser extent ornithine. Ketimine reductase is involved in several diseases | Homo sapiens |
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