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Literature summary for 1.1.1.141 extracted from

  • Uppal, S.; Diggle, C.P.; Carr, I.M.; Fishwick, C.W.; Ahmed, M.; Ibrahim, G.H.; Helliwell, P.S.; Latos-Biele?ska, A.; Phillips, S.E.; Markham, A.F.; Bennett, C.P.; Bonthron, D.T.
    Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy (2008), Nat. Genet., 40, 789-793.
    View publication on PubMed

Application

Application Comment Organism
medicine A140P is a naturally occuring mutation in patients with pulmonary hypertrophic osteoarthropathy. Homozygous individuals develop pulmonary hypertrophic osteoarthropathy secondary to chronically elevated prostaglandin E2 levels. Heterozygous relatives also show milder biochemical and clinical manifestations. Identification of an insertion-deletion mutation in 15-hydroxyprostaglandin dehydrogenase exon 3, this alters the open reading frame from codon 78, truncating the protein after ten altered amino acids, and of a homozygous 2-bp deletion within the duplicated dinucleotide CTCT at nucleotides 175 and 176. This alters the reading frame from residue 59 and truncates the HPGD protein at residue 65 after seven altered amino acids. Both of these predicted truncated proteins lack the entire PGE2-binding domain and cause primary hypertrophic osteoarthropathy Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
expressed in Escherichia coli strain JM109(DE3) Homo sapiens
expression in Escherichia coli Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
modeling of structure for mutant A140P. Mutation disrupts binding of the substrate prostaglandin E2 both because the pyrrolidine ring of Pro140 fills a space that in the wildtype complex is occupied by the prostaglandin E2 target side-chain 15-OH and because there is a resulting loss of catalytically important hydrogen bonding of the 15-OH to the nearby serine at residue 138 Homo sapiens

Protein Variants

Protein Variants Comment Organism
A140P naturally occuring mutation in patients with pulmonary hypertropic osteoarthropathy. Homozygous individuals develop pulmonary hypertrophic osteoarthropathy secondary to chronically elevated prostaglandin E2 levels. Heterozygous relatives also show milder biochemical and clinical manifestations. After expression in Escherichia coli, the mutations renders the protein largely insoluble at 37°C, but mostly souble at 20°C. Mutant exhibits less than 1.5% of wild-type activity Homo sapiens
A140P the mutant shows no detectable activity, the A140P substitution renders the enzyme largely insoluble at 37°C, at 27°C, the mutant protein is partially soluble, and at 20°C it is mostly soluble Homo sapiens
additional information identification of an insertion-deletion mutation in 15-hydroxyprostaglandin dehydrogenase exon 3, this alters the open reading frame from codon 78, truncating the protein after ten altered amino acids, and of a homozygous 2-bp deletion within the duplicated dinucleotide CTCT at nucleotides 175 and 176. This alters the reading frame from residue 59 and truncates the HPGD protein at residue 65 after seven altered amino acids. Both of these predicted truncated proteins lack the entire PGE2-binding domain and cause primary hypertrophic asteoarthropathy Homo sapiens

General Stability

General Stability Organism
the assay mix containing 50 mM Tris HCl, pH 7.5, 1 mM dithiothreitol, 100 mM prostaglandin E2 and 1 mM NAD+ at 22°C is not optimal for HPGD activity, but avoids a sharp, unphysiological pH optimum around pH 9 Homo sapiens

Molecular Weight [Da]

Molecular Weight [Da] Molecular Weight Maximum [Da] Comment Organism
31000
-
wild type recombinant protein, SDS-PAGE Homo sapiens

Organism

Organism UniProt Comment Textmining
Homo sapiens
-
-
-
Homo sapiens
-
patients with primary hypertrophic osteoarthropathy
-

Purification (Commentary)

Purification (Comment) Organism
nickel-Sepharose column chromatography Homo sapiens

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
prostaglandin E2 + NAD+ the wild type enzyme is highly active against prostaglandin E2 and NAD+ Homo sapiens 15-ketoprostaglandin E2 + NADH + H+
-
?

Synonyms

Synonyms Comment Organism
15-hydroxyprostaglandin dehydrogenase
-
Homo sapiens
HPGD
-
Homo sapiens
NAD+-dependent 15-hydroxyprostaglandin dehydrogenase
-
Homo sapiens

Temperature Stability [°C]

Temperature Stability Minimum [°C] Temperature Stability Maximum [°C] Comment Organism
37
-
when expression is induced at 37°C, almost all wild type recombinant HPGD protein is soluble Homo sapiens

Cofactor

Cofactor Comment Organism Structure
NAD+ dependent on Homo sapiens