Red cell glyoxalase I polymorphism in Italians. Report of a variant phenotype.

The glyoxalase I polymorphism was studied in 1,490 unrelated subjects from three different areas of Italy (Milan, Rome and Naples). The following frequencies of GLO2 allele were observed: Milan 0.57, Rome 0.59, Naples 0.61, and a significant difference between Milan and Naples was found (p less than 0.02). An anomalous phenotype is also described which permits us to postulate a new allele producing an isozyme with low activity and electrophoretically slower than those corresponding to GLO1 and GLO2 alleles.     

Human red cell glyoxalase I polymorphism in Denmark and its application to paternity cases.

Phenotypes of glyoxalase I (GLO) were determined in 1220 unrelated adults from all parts of Denmark giving the gene frequencies GLO1 = 0.4311 and GLO2 = 0.5689. The segregation of phenotypes in 59 families and in 455 mother-child pairs was consistent with the assumed autosomal codominant inheritance. The results of an investigation of 379 parternity cases with respect to exclusions of non-fathers by means of the GLO system are reported, and the application of the GLO system to paternity cases is discussed.     

Polymorphism of glyoxalase I in Vienna.

Phenotype and gene frequencies of the GLO I polymorphism in Vienna are given. No exception to the postulated rule of inheritance could be found in 23 families with 51 children and 132 mother-child pairs. Linkage with the HLA system is confirmed, but no linkage disequilibrium between GLO alleles and HLA-A, B, C genes was detected. The use of the GLO I polymorphism in paternity cases is discussed.     

Rapid detection of glyoxalase I (GLO) on cellulose acetate gel and the distribution of GLO variants in a Dutch population

Summary A rapid electrophoretic procedure is described for detecting the human red cell glyoxalase I variants (GLO 1, GLO 2-1, and GLO 2) on cellulose acetate gel (cellogel) on which the sites of enzymed activity are visualized as purple bands against white background. The frequency of GLO ¹ gene in a Dutch population living in and around Leiden was found to be 0.4544.     

Assignment of the gene for glyoxylase I to mouse chromosome 17 by somatic cell genetics

Evidence is presented for the assignment of the gene for glyoxylase I to mouse chromosome 17 using mouse × Chinese hamster somatic cell hybrids. GLO I was not expressed concordantly with any known marker enzymes which represented 11 linkage groups. The presence of chromosome 17 and expression of GLO I were concordant in 31/31 clones. GLO I is thus linked to the H-2 histocompatibility locus in the mouse.     

Genetic variability inCebus appella paraguayanus: Biochemical analysis of seven loci and variation in Glyoxalase I (E.C.4.4.1.5)

An analysis of seven loci inCebus apella paraguayanus showed that Glyoxalase I was polymorphic due the appearance of two alleles (GLO*2 andGLO*3) with frequencies of 0.955 and 0.045, respectively. Of the two alleles,GLO*2 was electrophoretically similar to the most common allele found in the human andAotus. These results confirmed our previous findings in the same population sample showing that this subspecies has a very low genetic variation among New World primates.     

A new rare variant of the glyoxalase I system of the red cell: GLO-Sicily

A fast variant of the red cell enzyme glyoxalase I was identified in a sample of 663 persons from Eastern Sicily; the allele was designated GLOSi. The gene frequencies for the common alleles GLO1 and GLO2 are not different from those observed in other southern Italian populations, and are in agreement with the hypothesis of a westward gene flow from Asia.     

Glyoxalase I polymorphism in Belgium

The phenotypes of red cell glyoxalase I (EC 4.4.1.5) were determined by cellogel electrophoresis in 750 Belgian persons. The gene frequencies found were 0.432 for GLO1 and 0.568 for GLO2.     

Polymorphism of red cell glyoxalase I in Serbia, Yugoslavia

Red cell glyoxalase I (GLO) phenotypes were determined in 258 unrelated adults from the population of Serbia (Yugoslavia). The GLO1 gene frequency was estimated to be 0.384.     

Piceatannol,a natural trans-stilbene compound,inhibits human glyoxalase I

Human glyoxalase I (GLO I), a rate-limiting enzyme for detoxification of methylglyoxal (MG), a by-product of glycolysis, is known to be a potential therapeutic target for cancer. Here, we searched new scaffolds from natural compounds for designing novel GLO I inhibitors and found trans-stilbene scaffold. We examined the inhibitory abilities to human GLO I of commercially available trans-stilbene compounds. Among them, piceatannol was found to have the most potent inhibitory activity against human GLO I. Piceatannol could inhibit the proliferation of human lung cancer NCI-H522 cells, which are dependent on GLO I for survival, in a dose- and time-dependent manner. In addition, piceatannol more significantly inhibited the proliferation of NCI-H522 cells than that of NCI-H460 cells, which are less dependent on GLO I. Importantly, overexpression of GLO I in NCI-H522 cells resulted in less sensitive to the antiproliferative activity of piceatannol. Taken together, this is the first report demonstrating that piceatannol inhibits GLO I activity and the GLO I-dependent proliferation of cancer cells. Furthermore, we determined a pharmacophore for novel inhibitors of human GLO I by computational simulation analyses of the binding mode of piceatannol to the enzyme hot spot in the active site. We suggest that piceatannol is a possible lead compound for the development of novel GLO I inhibitory anticancer drugs.     

Population genetics of glyoxalase I (GLO) polymorphism in India

Phenotype and gene frequency data are presented on the glyoxalase I (GLO) polymorphism in seven endogamous caste groups: Jat Sikh, Ramdasia Sikh, Ramgarhia Sikh, Khatri, Brahmin and Bania of Patiala district, and Jat Sikh of Faridkot district of Punjab, North-West India. Apparently, there is considerable heterogeneity in the frequency distribution of the GLO1 gene that varies from 0.168 in Bania to 0.287 in Brahmin. However, these differences are not statistically significant, and the overall GLO1 frequency in Punjab is well within the North Indian range.     

Structure-activity relationship of human GLO I inhibitory natural flavonoids and their growth inhibitory effects

Glyoxalase I (GLO I) is the rate-limiting enzyme for detoxification of methylglyoxal (MG), a side product of glycolysis, which is able to induce apoptosis. Since GLO I is known to be highly expressed in the most tumor cells and little in normal cells, specific inhibitors of this enzyme have been expected as effective anticancer drugs. The purpose of this study is a good construction of the human GLO I/inhibitor pharmacophore to obtain unique human GLO I inhibitory seed compounds for the development of useful anticancer drugs. Here, we selected natural flavonoid compounds that possess a plane configuration of cis C-4 ketone and C-5 hydroxy groups as the substrate (MG) transition-state mimetic structure. These compounds were examined the inhibitory abilities to human GLO I activity and analyzed their structure-activity relationships to determine an important pharmacophore of flavonoids for the human GLO I binding. Our results point to the contribution of hydroxy groups at the B ring of flavonoids to the effective inhibition of the human GLO I. Based on the binding mode of flavonoids, we constructed the human GLO I/inhibitor pharmacophore. This work delivers the first three-dimensional (3D) structural data and explains certain flavonoids interact specifically with the human GLO I.     

Recent advances in the discovery and development of glyoxalase I inhibitors

Glyoxalase I (GLO1) is a homodimeric Zn²⁺-metalloenzyme that catalyses the transformation of methylglyoxal (MG) to d-lacate through the intermediate S-d-lactoylglutathione. Growing evidence indicates that GLO1 has been identified as a potential target for the treatment cancer and other diseases. Various inhibitors of GLO1 have been discovered or developed over the past several decades including natural or natural product-based inhibitors, GSH-based inhibitors, non-GSH-based inhibitors, etc. The aim of this review is to summarize recent achievements of concerning discovery, design strategies, as well as pharmacological aspects of GLO1 inhibitors with the target of promoting their development toward clinical application.     

Specificity of the trypanothione-dependent Leishmania major glyoxalase I: structure and biochemical comparison with the human enzyme

Trypanothione replaces glutathione in defence against cellular damage caused by oxidants, xenobiotics and methylglyoxal in the trypanosomatid parasites, which cause trypanosomiasis and leishmaniasis. In Leishmania major, the first step in methylglyoxal detoxification is performed by a trypanothione-dependent glyoxalase I (GLO1) containing a nickel cofactor; all other characterized eukaryotic glyoxalases use zinc. In kinetic studies L. major and human enzymes were active with methylglyoxal derivatives of several thiols, but showed opposite substrate selectivities: N1-glutathionylspermidine hemithioacetal is 40-fold better with L. major GLO1, whereas glutathione hemithioacetal is 300-fold better with human GLO1. Similarly, S-4-bromobenzylglutathionylspermidine is a 24-fold more potent linear competitive inhibitor of L. major than human GLO1 (Kis of 0.54 microM and 12.6 microM, respectively), whereas S-4-bromobenzylglutathione is >4000-fold more active against human than L. major GLO1 (Kis of 0.13 microM and >500 microM respectively). The crystal structure of L. major GLO1 reveals differences in active site architecture to both human GLO1 and the nickel-dependent Escherichia coli GLO1, including increased negative charge and hydrophobic character and truncation of a loop that may regulate catalysis in the human enzyme. These differences correlate with the differential binding of glutathione and trypanothione-based substrates, and thus offer a route to the rational design of L. major-specific GLO1 inhibitors.     

我国汉族人群的乙二醛酶Ⅰ遗传多态性

用琼脂糖平板凝胶电泳技术分析了我国六个城市的汉族共1238人的红细胞乙二醛酶I的遗传多态性。每个汉族人群的受检人数和GLO1*1基因频率分别为:郑州200人(0.1023),哈尔滨195人(0.1103),呼和浩特210人(0.1259),贵阳204人(0.1373),兰州210人(0.1476),西安199人(0.1508)。中国不同地区汉族人群之间的GLOI基因频率分布存在显著性差异,但这种差异明显小于中国不同少数民族之间的差异。     

Glyoxalase-I is a novel prognosis factor associated with gastric cancer progression

Glyoxalase I (GLO1), a methylglyoxal detoxification enzyme, is implicated in the progression of human malignancies. The role of GLO1 in gastric cancer development or progression is currently unclear. The expression of GLO1 was determined in primary gastric cancer specimens using quantitative polymerase chain reaction, immunohistochemistry (IHC), and western blotting analyses. GLO1 expression was higher in gastric cancer tissues, compared with that in adjacent noncancerous tissues. Elevated expression of GLO1 was significantly associated with gastric wall invasion, lymph node metastasis, and pathological stage, suggesting a novel role of GLO1 in gastric cancer development and progression. The 5-year survival rate of the lower GLO1 expression groups was significantly greater than that of the higher expression groups (log rank P = 0.0373) in IHC experiments. Over-expression of GLO1 in gastric cancer cell lines increases cell proliferation, migration and invasiveness. Conversely, down-regulation of GLO1 with shRNA led to a marked reduction in the migration and invasion abilities. Our data strongly suggest that high expression of GLO1 in gastric cancer enhances the metastasis ability of tumor cells in vitro and in vivo, and support its efficacy as a potential marker for the detection and prognosis of gastric cancer.     

Study of the variability of erythrocyte enzymes in captive and wild populations of the black lemur (Eulemur macaco macaco). An indispensable preliminary in captive breeding programmes

A study of ten erythrocyte enzymes (PGM I, II, III, G6PD, 6PGD, GLO I, ADA, Est D, DIA, AcP, CA II, and AK) performed on 89 wild and 32 captiveEulemur macaco macaco shows that most systems are monomorphic except four (GLO I, CA II, 6PGD, and NADH DIA). The polymorphism of these markers allows us to make a satisfactory analysis of the variability on this species, especially on the view of comparing wild and captive populations, and shows that: (1) the population does not contain all phenotypes existing in the wild CA_a, CA_{a + b}, DIA_IV, GLO I_{B − C}, and PGD_c are completely absent in all captive populations and DIA_{III + IV} is only present in three out of 32 animals; (2) in the Nosy-komba Island, the PGD_c and DIA_IV are absent and DIA_{III + IV} and GLO I_{B − C} are only present in 1 out of 46 analyzed samples, showing that this population constitutes an isolate. The possibility to use these data for a strategy of Lemur conservation is discussed.     

Polymorphism of human red cell glyoxalase I in six ethnic groups of China

Summary A total of 1242 individuals from six Chinese ethnic groups were studied with respect to the glyoxalase I polymorphism using agarose gel electrophoresis. The GLO1^*1 gene frequency and the number of subjects tested in each population are as follows: Uygur 0.2466 (219), Hui 0.1621 (219), Dong 0.1866 (201), Bai 0.1921 (203), Tujia 0.1075 (200), and Maio 0.1600 (200). The differences in the GLO1 gene frequencies between some of these populations are significant.