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Literature summary extracted from

  • Patel, S.; Seravalli, J.; Liang, X.; Tanner, J.; Becker, D.
    Disease variants of human Delta1-pyrroline-5-carboxylate reductase 2 (PYCR2) (2021), Arch. Biochem. Biophys., 703, 108852 .
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

EC Number Cloned (Comment) Organism
1.5.1.2 gene PYR2, recombinant expression of His-tagged wild-type and mutant enzymes in Escherichia coli strain BL21 (DE3) pLysS Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
1.5.1.2 R119C mutation identified in patient with microcephaly and hypomyelination, mutant is catalytically impaired Homo sapiens
1.5.1.2 R119C a naturally occuring mutation in patients with microcephaly and hypomyelination. The mutant is catalytically impaired, depending on whether NADPH or NADH is used, the catalytic efficiency of the R119C protein variant is 40 or 366 times lower than that of the wild-type enzyme Homo sapiens
1.5.1.2 R251C mutation identified in patient with microcephaly and hypomyelination, mutant is catalytically impaired and has a pronounced folding defect Homo sapiens
1.5.1.2 R251C a naturally occuring mutation in patients with microcephaly and hypomyelination. The mutant is catalytically impaired, depending on whether NADPH or NADH is used, the catalytic efficiency of the R119C protein variant is 7 or 26 times lower than that of the wild-type enzyme. The R251C protein variant has a pronounced folding defect. The R251C variant displays the least overall regular alpha-helical character of the PYCR2 proteins, yet the R251C variant also displays strong overall regular beta-strand or beta-sheet character Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.2 L-proline at 0-500 microM, the value of KMapp increases whereas Vlim remains fairly unchanged, which is consistent with competitive inhibition Homo sapiens

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
1.5.1.2 additional information
-
 additional information steady-state kinetics of the wild-type enzyme and mutants Homo sapiens
1.5.1.2 0.03
-
 NADH mutant R119C, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.034
-
 NADH pH 7.5, 37°C, recombinant mutant R119C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 0.119
-
 NADPH pH 7.5, 37°C, recombinant mutant R251C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 0.12
-
 NADPH mutant R251C, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.216
-
 NADPH pH 7.5, 37°C, recombinant wild-type enzyme, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 0.22
-
 NADPH wild-type, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.298
-
 NADH pH 7.5, 37°C, recombinant wild-type enzyme, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 0.3
-
 NADH wild-type, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.317
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R119C, with NADH Homo sapiens
1.5.1.2 0.32
-
 1-pyrroline-5-carboxylate mutant R119C, cosubstrate NADH, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.33
-
 1-pyrroline-5-carboxylate mutant R119C, cosubstrate NADPH, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.334
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R119C, with NADPH Homo sapiens
1.5.1.2 0.537
-
 NADPH pH 7.5, 37°C, recombinant mutant R119C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 0.54
-
 NADPH mutant R119C, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.949
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant wild-type enzyme, with NADPH Homo sapiens
1.5.1.2 0.95
-
 NADH mutant R251C, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.953
-
 NADH pH 7.5, 37°C, recombinant mutant R251C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 0.99
-
 1-pyrroline-5-carboxylate wild-type, cosubstrate NADPH, pH 7.5, 37°C Homo sapiens
1.5.1.2 1.315
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R251C, with NADH Homo sapiens
1.5.1.2 1.32
-
 1-pyrroline-5-carboxylate mutant R251C, cosubstrate NADH, pH 7.5, 37°C Homo sapiens
1.5.1.2 1.499
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R251C, with NADPH Homo sapiens
1.5.1.2 1.5
-
 1-pyrroline-5-carboxylate mutant R251C, cosubstrate NADPH, pH 7.5, 37°C Homo sapiens
1.5.1.2 1.509
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant wild-type enzyme, with NADH Homo sapiens
1.5.1.2 1.51
-
 1-pyrroline-5-carboxylate wild-type, cosubstrate NADH, pH 7.5, 37°C Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
1.5.1.2 mitochondrion
-
 Homo sapiens 5739
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.5.1.2 1-pyrroline-5-carboxylate + NADH + H+ Homo sapiens
-
 L-proline + NAD+
-
 ?
1.5.1.2 1-pyrroline-5-carboxylate + NADPH + H+ Homo sapiens
-
 L-proline + NADP+
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.2 Homo sapiens Q96C36
-
-
1.5.1.2 Homo sapiens Q96C36 isoform PYRC2
-

Purification (Commentary)

EC Number Purification (Comment) Organism
1.5.1.2 recombinant His-tagged wild-type and mutant enzymes from Escherichia coli strain BL21 (DE3) pLysS by nickel affinity chromatography, dialysis, and ultrafiltration Homo sapiens

Reaction

EC Number Reaction Comment Organism Reaction ID
1.5.1.2 L-proline + NAD(P)+ = 1-pyrroline-5-carboxylate + NAD(P)H + H+ enzyme PYCR2 kinetics suggest a sequential binding mechanism with L-P5C binding before NAD(P)H and NAD(P)+ releasing before L-Pro Homo sapiens
a

Source Tissue

EC Number Source Tissue Comment Organism Textmining
1.5.1.2 epithelium
-
 Homo sapiens
-
1.5.1.2 esophageal squamous cell carcinoma cell
-
 Homo sapiens
-
1.5.1.2 skeletal muscle
-
 Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.5.1.2 1-pyrroline-5-carboxylate + NADH
-
 Homo sapiens L-proline + NAD+
-
 ?
1.5.1.2 1-pyrroline-5-carboxylate + NADH + H+
-
 Homo sapiens L-proline + NAD+
-
 ?
1.5.1.2 1-pyrroline-5-carboxylate + NADPH
-
 Homo sapiens L-proline + NADP+
-
 ?
1.5.1.2 1-pyrroline-5-carboxylate + NADPH + H+
-
 Homo sapiens L-proline + NADP+
-
 ?

Synonyms

EC Number Synonyms Comment Organism
1.5.1.2 DELTA1-pyrroline-5-carboxylate reductase 2
-
 Homo sapiens
1.5.1.2 PYCR2
-
 Homo sapiens

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
1.5.1.2 37
-
 assay at Homo sapiens

Temperature Stability [°C]

EC Number Temperature Stability Minimum [°C] Temperature Stability Maximum [°C] Comment Organism
1.5.1.2 54 79 PYCR2 wild-type and mutant R119C exhibit fairly sharp unfolding transitions and similar Tm values of 69°C and 67°C, respectively, whereas mutant R251C exhibits a dramatically lower Tm value of 54°C. Incubation of each PYCR2 enzyme with product ligands, L-Pro and NAD+, individually or together has no effect on the observed Tm values Homo sapiens

Turnover Number [1/s]

EC Number Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
1.5.1.2 0.015
-
 NADH mutant R119C, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.015
-
 NADH pH 7.5, 37°C, recombinant mutant R119C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 0.08
-
 1-pyrroline-5-carboxylate mutant R119C, cosubstrate NADH, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.08
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R119C, with NADH Homo sapiens
1.5.1.2 0.13
-
 1-pyrroline-5-carboxylate mutant R119C, cosubstrate NADPH, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.13
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R119C, with NADPH Homo sapiens
1.5.1.2 1.5
-
 NADPH mutant R119C, pH 7.5, 37°C Homo sapiens
1.5.1.2 1.5
-
 NADPH pH 7.5, 37°C, recombinant mutant R119C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 1.8
-
 NADPH mutant R251C, pH 7.5, 37°C Homo sapiens
1.5.1.2 1.8
-
 NADPH pH 7.5, 37°C, recombinant mutant R251C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 3.1
-
 1-pyrroline-5-carboxylate mutant R251C, cosubstrate NADPH, pH 7.5, 37°C Homo sapiens
1.5.1.2 3.1
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R251C, with NADPH Homo sapiens
1.5.1.2 3.2
-
 1-pyrroline-5-carboxylate mutant R251C, cosubstrate NADH, pH 7.5, 37°C Homo sapiens
1.5.1.2 3.2
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R251C, with NADH Homo sapiens
1.5.1.2 5.9
-
 NADH mutant R251C, pH 7.5, 37°C Homo sapiens
1.5.1.2 5.9
-
 NADH pH 7.5, 37°C, recombinant mutant R251C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 24
-
 NADPH wild-type, pH 7.5, 37°C Homo sapiens
1.5.1.2 24
-
 NADPH pH 7.5, 37°C, recombinant wild-type enzyme, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 26
-
 1-pyrroline-5-carboxylate wild-type, cosubstrate NADPH, pH 7.5, 37°C Homo sapiens
1.5.1.2 26
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant wild-type enzyme, with NADPH Homo sapiens
1.5.1.2 47.9
-
 NADH wild-type, pH 7.5, 37°C Homo sapiens
1.5.1.2 47.9
-
 NADH pH 7.5, 37°C, recombinant wild-type enzyme, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 61.3
-
 1-pyrroline-5-carboxylate wild-type, cosubstrate NADH, pH 7.5, 37°C Homo sapiens
1.5.1.2 61.3
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant wild-type enzyme, with NADH Homo sapiens

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
1.5.1.2 7.5
-
 assay at Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
1.5.1.2 additional information PYCR2 does not show a strong preference for NADH or NADPH Homo sapiens
1.5.1.2 NAD+
-
 Homo sapiens
1.5.1.2 NADH
-
 Homo sapiens
1.5.1.2 NADP+
-
 Homo sapiens
1.5.1.2 NADPH
-
 Homo sapiens

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
1.5.1.2 additional information
-
 additional information product(s) inhibition kinetics are analyzed by global fitting of the data to different inhibition models Homo sapiens
1.5.1.2 0.145
-
 L-proline pH 7.5, 37°C, recombinant wild-type enzyme, competitive inhibition Homo sapiens

Expression

EC Number Organism Comment Expression
1.5.1.2 Homo sapiens in a mass spectrometry-based screening of metabolites in tissue sections from 256 esophageal squamous cell carcinoma (ESCC) patients, a significant upregulation of L-proline metabolism is found in the cancer region compared to the normal epithelium and muscle regions. Immunohistochemistry staining of the ESCC tissue sections identifies PYCR2 as the most enriched metabolic enzyme in the cancer region, consistent with increased L-proline found in the same tissue region up

General Information

EC Number General Information Comment Organism
1.5.1.2 malfunction homozygous mutations in human PYCR2 lead to postnatal microcephaly and hypomyelination, including hypomyelinating leukodystrophy type 10. PYCR2 mutations are detected in patients with lethal microcephaly, loss of PYCR2 is proposed to impair mitochondria function and disrupt oxidative balance, namely NAD(P)+ levels. The R251C variant displays the least overall regular alpha-helical character of the PYCR2 proteins, yet the R251C variant also displays strong overall regular beta-strand or beta-sheet character Homo sapiens
1.5.1.2 metabolism sequential binding mechanism with 1-pyrroline-5-carboxylate binding before NAD(P)H and NAD(P)+ releasing before L-Pro Homo sapiens
1.5.1.2 metabolism the enzyme is involved in the proline metabolism in the mitochondrion, overview Homo sapiens
1.5.1.2 physiological function pyrroline-5-carboxylate reductase (PYCR in humans) catalyzes the final step of L-proline biosynthesis by catalyzing the reduction of L-DELTA1-pyrroline-5-carboxylate (L-P5C) to L-proline using NAD(P)H as the hydride donor. In humans, three isoforms PYCR1c, and PYCR3 are known. Isozyme PYCR3 is a cytosolic enzyme whereas PYCR1 and PYCR2 are identified as mitochondrial isozymes. PYCR2 not only drives cellular supply of L-proline but it is also important for redox cycling of NAD(P)H/NAD(P)+ Homo sapiens

kcat/KM [mM/s]

EC Number kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
1.5.1.2 0.25
-
 1-pyrroline-5-carboxylate mutant R119C, cosubstrate NADH, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.25
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R119C, with NADH Homo sapiens
1.5.1.2 0.39
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R119C, with NADPH Homo sapiens
1.5.1.2 0.4
-
 1-pyrroline-5-carboxylate mutant R119C, cosubstrate NADPH, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.44
-
 NADH mutant R119C, pH 7.5, 37°C Homo sapiens
1.5.1.2 0.441
-
 NADH pH 7.5, 37°C, recombinant mutant R119C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 2.07
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R251C, with NADPH Homo sapiens
1.5.1.2 2.1
-
 1-pyrroline-5-carboxylate mutant R251C, cosubstrate NADPH, pH 7.5, 37°C Homo sapiens
1.5.1.2 2.4
-
 1-pyrroline-5-carboxylate mutant R251C, cosubstrate NADH, pH 7.5, 37°C Homo sapiens
1.5.1.2 2.43
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant mutant R251C, with NADH Homo sapiens
1.5.1.2 2.793
-
 NADPH pH 7.5, 37°C, recombinant mutant R119C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 2.8
-
 NADPH mutant R119C, pH 7.5, 37°C Homo sapiens
1.5.1.2 6.19
-
 NADH pH 7.5, 37°C, recombinant mutant R251C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 6.2
-
 NADH mutant R251C, pH 7.5, 37°C Homo sapiens
1.5.1.2 15
-
 NADPH mutant R251C, pH 7.5, 37°C Homo sapiens
1.5.1.2 15.13
-
 NADPH pH 7.5, 37°C, recombinant mutant R251C, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 26
-
 1-pyrroline-5-carboxylate wild-type, cosubstrate NADPH, pH 7.5, 37°C Homo sapiens
1.5.1.2 27.4
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant wild-type enzyme, with NADPH Homo sapiens
1.5.1.2 40.62
-
 1-pyrroline-5-carboxylate pH 7.5, 37°C, recombinant wild-type enzyme, with NADH Homo sapiens
1.5.1.2 41
-
 1-pyrroline-5-carboxylate wild-type, cosubstrate NADH, pH 7.5, 37°C Homo sapiens
1.5.1.2 111
-
 NADPH wild-type, pH 7.5, 37°C Homo sapiens
1.5.1.2 111.11
-
 NADPH pH 7.5, 37°C, recombinant wild-type enzyme, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 160.74
-
 NADH pH 7.5, 37°C, recombinant wild-type enzyme, with 1-pyrroline-5-carboxylate Homo sapiens
1.5.1.2 161
-
 NADH wild-type, pH 7.5, 37°C Homo sapiens