Disease relevance of PRODH

• In two unrelated patients suffering from severe type I hyperprolinemia with neurological manifestations, we identified a homozygous L441P PRODH mutation, associated with a heterozygous R453C substitution in one patient [1].
• We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders [2].
• Here we present a structure-based study of the PRODH active site of the multifunctional Escherichia coli proline utilization A (PutA) protein using X-ray crystallography, enzyme kinetic measurements, and site-directed mutagenesis [3].

Psychiatry related information on PRODH

• These observations demonstrate that type I hyperprolinemia is present in a subset of schizophrenic patients, and suggest that the genetic determinism of type I hyperprolinemia is complex, the severity of hyperprolinemia depending on the nature and number of hits affecting the PRODH locus [1].
• As part of the evaluation of their roles in psychosis, we used reverse transcription-polymerase chain reaction to measure COMT and PRODH mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, major depression, and normal controls (n = 15 subjects in each group) [4].
• This is the first study on a potential involvement of the proline dehydrogenase locus in bipolar affective disorder [5].

High impact information on PRODH

• PRODH is localized at chromosome 22q11 in a region deleted in some psychiatric patients [6].
• Our observations, in conjunction with the chromosomal location of PRODH, suggest a potential involvement of this gene in the 22q11-associated psychiatric and behavioural phenotypes [6].
• Functional consequences of PRODH missense mutations [7].
• The structure is a domain-swapped dimer with each subunit comprising three domains: a helical dimerization arm, a 120-residue domain containing a three-helix bundle similar to that in the helix-turn-helix superfamily of DNA-binding proteins and a beta/alpha-barrel PRODH domain with a bound lactate inhibitor [8].
• The human homolog of the PutA proline dehydrogenase (PRODH) domain is critical in p53-mediated apoptosis and schizophrenia [8].

Chemical compound and disease context of PRODH

• Prompted by the discovery of an apparent L-lactate molecule bound in the active site of the Escherichia coli PutA proline dehydrogenase domain crystal structure, the L-lactate concentration of several PEG solutions was measured [9].

Biological context of PRODH

• This is a sub-haplotype of the PRODH haplotype previously associated with schizophrenia and it also maps to the 3' region of the gene, indicating that this is the region most likely to contain the underlying risk alleles [10].
• In addition, two heterozygous PRODH missense mutations (L441P and L289M), detected in 3 of 63 schizophrenic patients but in none among 68 controls, were also associated with increased plasma proline levels [1].
• As COMT and PRODH are both located on chromosome 22q11, the results also argue against the hypothesis that schizophrenia is associated with a decrease in expression of all 22q11 genes, as had been suggested by the high prevalence of psychosis in people with hemizygous 22q11 deletions [4].
• Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes [2].
• Here we identify molecular interactions in the PutA PRODH active site that underlie redox-dependent functional switching of PutA [11].

Anatomical context of PRODH

• We conclude that any involvement of COMT and PRODH genes in schizophrenia is not accompanied by significant alterations in their overall mRNA expression, at least in dorsolateral prefrontal cortex [4].
• Further, based on plate assay, the likely mode of action may be through urease inhibition and disruption of energy production by inhibition of proline dehydrogenase at the plasma membrane [12].
• Key enzymes in proline and ornithine oxidation, i.e. proline dehydrogenase, pyrroline-carboxylate dehydrogenase, ornithine aminotransferase, and glutamate dehydrogenase were located in the mitochondria [13].
• Studies on the inner mitochondrial membrane localization of proline dehydrogenase [14].
• 1. The site of proline dehydrogenase (EC 1.5.99.-) activity in blowfly (Phormia regina) flight muscle mitochondria has been investigated employing the inner membrane-impermeable Fe(CN)63-as electron acceptor [14].

Associations of PRODH with chemical compounds

• Structures of the PutA PRODH domain complexed with competitive inhibitors acetate (K(i) = 30 mM), L-lactate (K(i) = 1 mM), and L-tetrahydro-2-furoic acid (L-THFA, K(i) = 0.2 mM) have been determined to high-resolution limits of 2.1-2.0 A [3].
• We report that reduction of the PRODH domain induces major structural changes in the FAD cofactor, including a 22 degrees bend of the isoalloxazine ring along the N(5)-N(10) axis, crankshaft rotation of the upper part of the ribityl chain, and formation of a new hydrogen bond network involving the ribityl 2'-OH group, FAD N(1), and Gly435 [11].
• Proline dehydrogenase (PRODH) catalyzes the first step of proline catabolism, the flavin-dependent oxidation of proline to Delta(1)-pyrroline-5-carboxylate [3].
• 3. The controls on metabolism in flight muscle, i.e. (1) glycogenolysis at phosphorylase and phosphorylase kinase, (2) glycolysis at phosphofructokinase, (3) alpha-glycerophosphate dehydrogenase, (4) proline dehydrogenase and (5) tricarboxylate cycle at isocitrate dehydrogenase, are effected by the phosphate potential and/or Ca2+ [15].
• To characterize transcriptional regulation of the key proline cycle enzymes in alfalfa (Medicago sativa), two proline dehydrogenase (MsPDH) genes and a partial sequence of Delta (1) -pyrroline-5-carboxylate dehydrogenase (MsP5CDH) gene were identified and cloned [16].

Other interactions of PRODH

• Neither COMT nor PRODH mRNA abundance differed between diagnostic groups, nor when controls were compared with all psychotic patients [4].
• In three independent samples, we provide evidence for a contribution of the PRODH2/DGCR6 locus in 22q11-associated schizophrenia [17].
• COMT and TBX1 were deleted in all 44 subjects, and PRODH in 40 subjects (19 SZ, 21 NP) [18].

References