The major cytosolic aldehyde dehydrogenase isozyme (ALDH1) exhibits strong activity for oxidation of retinal to retinoic acid, while the major mitochondrial ALDH2 and the stomach cytosolic ALDH3 have no such activity. The K(m) of ALDH1 for retinal is about 0.06 μmol/l at pH 7.5, and the catalytic efficiency (Vmax/Km) for retinal is about 600 times higher than that for acetaldehyde. Thus, ALDH1 can efficiently produce retinoic acid from retinal in tissues with low retinal concentrations (<0.1 μmol/l). The gene for ALDH1 has hormone response elements. These findings suggest that the major physiological substrate of human ALDH1 is retinal, and that its primary biological role is generation of retinoic acid resulting in modulation of cell differentiation including hormone-mediated development.

GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.

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This report describes the results of the analyses of PROs and patient-related electronic health record data collected under standard of care from cancer patients at outpatient pain management clinics of Anesthesiology and Palliative Care at the Memorial Sloan Kettering Cancer Center. Consideration of sex and age as predictors of opioid use is critical in attempting to understand PROs and their relationship to pain management.

Although mitochondrial aldehyde dehydrogenase (ALDH2) has been thought to play a major role in acetaldehyde detoxification, and the high incidence of 'alcohol flushing' among Orientals is attributed to the inherited deficiency of ALDH2, the role of cytosolic aldehyde dehydrogenase (ALDH1) cannot be ignored. On the premise that alcohol flushing in Caucasians could be related to ALDH1 abnormalities, we examined the enzyme properties and electrophoretic mobilities of ALDH1 partially purified from red blood cells of nine unrelated alcohol flushers. One exhibited very low activity (10-20% of control level), and another exhibited moderately low activity (60%) and altered kinetic properties. The electrophoretic mobilities of these two samples were also distinguishable from the control samples. Immunological quantitation indicated that the amounts of ALDH1 protein in these two samples were not reduced in parallel with their enzyme deficiency. In the first case, the two characteristics, i.e. very low enzyme activity and alcohol flushing, were inherited by her daughter.

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Human aldehyde dehydrogenase-5 gene (originally named as ALDHX) is expressed in liver and testis. The ALDH5 does not contain introns in the coding sequence for 517 amino acid residues. Within a short nucleotide region of the gene, the following three nucleotide changes were found in high frequencies, i.e., a silent C<-->T at nucleotide (nt) 183, C<-->T at nt 257 associated with a Val<-->Ala substitution, and T<-->G at nt 320 associated with a Arg<-->Leu substitution. The frequency of C at nt 183 is 81% in Caucasians and 65% in Japanese, and the difference is statistically not significant. The frequency of C at nt 257 is 76% in Caucasians and 55% in Japanese, and the difference is statistically significant (P = 0.02). The frequency of T at nt 320 is 71% in Caucasians, while it is only 27% in Japanese. The racial difference at nt 320 is highly significant (P < 0.001). No significant difference was found in the genotypes of the three nucleotide positions between alcoholic and nonalcoholic Caucasians within the limited numbers of subjects examined.

The X-chromosome-linked phosphoglycerate kinase (PGK) deficiency associated with severe chronic and acute haemolytic anaemia and mental disorders was first described in a large Chinese kindred in 1969. The molecular abnormality of this original variant remained to be identified. The red cell PGK activity was only about 5%, but the activity of the patients' lymphoblastoid cells was about 15% of normal. The PGK mRNA content of the patients' lymphoblastoid cells were normal. Analysis of the patients' mRNA showed the existence of a nucleotide transversion A-->T at position 491 (counting from adenine of the initiation codon). The mutation should cause an amino acid substitution Asp-->Val at position 163 of the enzyme. The replacement of the acidic aspartic acid by a hydrophobic valine is expected to induce drastic structural instability resulting in severe enzyme deficiency in the patients' tissues. The genotypes of two affected males, their mothers and 22 females of the family were identified by the PCR-mediated method using their genomic DNA samples. 13/24 females examined were found to be variant heterozygous. In this large family, affected males over three generations have died at a pre-adult age. Post- and pre-natal genotyping of the family members may prevent future problems.