Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In animals, UTP feedback inhibition of carbamyl phosphate synthetase II (CPSase) controls pyrimidine biosynthesis. Suppressor of black (Su(b) or rSu(b)) mutants of Drosophila melanogaster have elevated pyrimidine pools, and this mutation has been mapped to the rudimentary locus. We report that rSu(b) is a missense mutation resulting in a glutamate to lysine substitution within the second ATP binding site (i.e. CPS.B2 domain) of CPSase. This residue corresponds to Glu780 in the Escherichia coli enzyme (Glu1153 in hamster CAD) and is universally conserved among CPSases. When a transgene expressing the Glu-->Lys substitution was introduced into Drosophila lines homozygous for the black mutation, the resulting flies exhibited the Su(b) phenotype. Partially purified CPSase from rSu(b) and transgenic flies carrying this substitution exhibited a dramatic reduction in UTP feedback inhibition. The slight UTP inhibition observed with the Su(b) enzyme in vitro was due mainly to chelation of Mg2+ by UTP. However, the Km values for glutamate, bicarbonate, and ATP obtained from the Su(b) enzyme were not significantly different from wild-type values. From these experiments, we conclude that this residue plays an essential role in the UTP allosteric response, probably in propagating the response between the effector binding site and the ATP binding site. This is the first CPSase mutation found to abolish feedback inhibition without significantly affecting other enzyme catalytic parameters.
J Mol Biol 1999 Mar 26
PMID:A mutation that uncouples allosteric regulation of carbamyl phosphate synthetase in Drosophila. 1008 Aug 91

Background: Three common alleles of apolipoprotein E (apoE) have been identified and are expressed codominantly to generate six genotypes. Different apoE genotypes are implicated in several cardiovascular and neurologic disorders. Testing for apoE genotypes has increasing diagnostic importance, particularly in the risk assessment of coronary artery disease. A reproducible and cost-effective assay was developed. Methods and Results: Polymerase chain reaction (PCR) amplification of the fourth exon of the apoE gene is performed in the presence of dimethyl sulfoxide using two-step thermal cycling. The PCR products are digested with HhaI restriction enzyme and analyzed by agarose gel electrophoresis to determine apoE genotypes. Effects of several factors, including dimethyl sulfoxide, DNA concentration, and PCR cycling conditions, on PCR specificity and efficiency have been determined and optimized. Conclusions: Apolipoprotein E genotyping by a PCR restriction fragment length polymorphism analysis has been optimized for use in a clinical diagnostic laboratory, allowing evaluation of up to 52 samples by one technician in one day.
Mol Diagn 1997 Dec
PMID:Optimization of Apolipoprotein E Genotyping. 1046 19

We examined associations between the endothelial nitric oxide synthase (eNOS) gene Glu-298-->Asp (894G-->T) mutation and the occurrence and severity of angiographically defined coronary artery disease (CAD). eNOS mediates basal vascular wall nitric oxide production, and altered nitric oxide production has been implicated in atherosclerosis. The newly identified eNOS Glu-298-->Asp mutation in exon 7 is common and likely to be functional. It was found to be associated with myocardial infarction (MI) in Japanese but not in whites. We genotyped 763 white Australians undergoing coronary angiography for the eNOS Glu-298-->Asp mutation. The frequencies of the eNOS GG, TG and TT genotypes were 47.8%, 41.2% and 11.0% in men and 45.2%, 41.1% and 13.7% in women with CAD, and were not significantly different from those without CAD (43.2%, 40.7% and 16.0%, P=0.423 in men; 40.2%, 48.1% and 11.7%, P=0.582 in women). The mutation was also not associated with MI (P=0.469 in males; P=0.389 in females) or with the number of significantly stenosed vessels (P=0.954; P=0.734). The "T" allele frequency (32.5%) was much greater than that reported for the Japanese population (7.8% in controls and 10.0% in MI patients). In conclusion, the eNOS Glu-298-->Asp mutation is common, occurring with an allele frequency of 32.5%, but is not associated with either the occurrence or severity of CAD in the Australian population or with other established coronary risk factors assessed in our study. The mutation is significantly more frequent in the Australian than in the Japanese.
J Mol Med (Berl) 1999 Jun
PMID:The Glu-298-->Asp (894G-->T) mutation at exon 7 of the endothelial nitric oxide synthase gene and coronary artery disease. 1047 66

Depression represents a major public health problem. It is estimated that 13-20% of the population has some depressive symptoms at any given time and about 5% of the population is assumed to suffer from major depression. Known pathological processes include ischemia, neoplasia, necrosis, apoptosis, infection, and inflammation. Of those, inflammation is the most compatible with the waxing and waning course of depression, and could explain the biology of this disorder that has a fluctuating course with severe episodes that can be followed by partial or complete remission. Over the years a body of evidence has been accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Major depression commonly co-occurs with ischemic heart disease and decreased bone mineral density. Depressive symptoms are known to have a negative impact on cardiovascular prognosis, increasing the mortality rate of coronary artery disease. Several lines of evidence indicate that brain cytokines, principally interleukin-1beta (IL-1beta) and IL-1 receptor antagonist may have a role in the biology of major depression, and that they might additionally be involved in the pathophysiology and somatic consequences of depression as well as in the effects of antidepressant treatment. A particularly unique and novel aspect of the studies and views discussed here is their potential to lead to interventions which may reduce the morbidity and mortality risks for osteoporosis, cardiovascular disease, and behavioral symptoms in patients with major depression. We also discuss the emerging concept of peripheral and central cytokine compartments: their integration and differential regulation is a key element for the optimal functioning of the immune and nervous systems.
Mol Psychiatry 1999 Jul
PMID:The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. 1048 47

Previously, we have used a chromatin cross-linking and immunoprecipitation protocol for the analysis of Myc and USF binding to the cad promoter. The adaptation of this technique for the study of mammalian transcription factors was a big step forward in the analysis of transcription factor family member specificity, allowing for the first time a definitive knowledge of which factor binds to a promoter region under normal physiological conditions. However, due to limitations of the assay, our previous studies could not definitively prove that both Myc and USF bound to the exact same site on the cad promoter, nor could we directly correlate loss of in vivo binding of a particular factor with loss of transcriptional activity. Therefore, we have further modified the chromatin immunoprecipitation protocol to alleviate these problems. We have now shown that it is possible to coexamine growth-regulated transcriptional activity and promoter occupancy by using stably integrated promoter constructs. We show that both Myc and USF bind to the exact same E box on the cad promoter, suggesting that competition between these two factors for a single site occurs in living cells. We also find that cad promoter constructs that retain USF binding but lose Myc binding in vivo no longer display an increase in transcriptional activity in mid- to late G(1) phase of the cell cycle. Finally, we propose that cell cycle-regulated transcriptional activation of the cad promoter may be a stochastic, rather than a predetermined, process.
Mol Cell Biol 1999 Dec
PMID:Coexamination of site-specific transcription factor binding and promoter activity in living cells. 1056 64

A lucerne (alfalfa, Medicago sativa) stem cDNA library was screened with a cinnamyl-alcohol dehydrogenase (CAD) cDNA probe from tobacco (Nicotiana tabacum cv. Samsun). Two distinctly different cDNA clones (54% identical) were isolated and identified as putative CAD-encoding cDNAs by comparison of their nucleotide sequences with those of CAD-encoding DNA sequences from other plant species. One of the cDNAs, MsaCad2, was found to be 99.4% identical at the nucleotide level to the previously isolated lucerne cad cDNA which encodes a CAD isoform involved in lignin biosynthesis. The other cDNA, MsaCad1, has not been reported previously in lucerne, and encodes a protein related to the ELI3 class of elicitor-inducible defence-related plant proteins. The MsaCad1- and MsaCad2-encoded proteins were expressed in Escherichia coli and CAD1 was shown to be active with a range of cinnamyl, benzyl and aliphatic aldehyde substrates, while CAD2 was specific for the cinnamyl aldehydes only. Each of the respective genes is present as one or two copies. The MsaCad1 gene is expressed most actively in stem and floral tissue, whereas MsaCad2 is most actively expressed in stem, hypocotyl and root tissue. In stem tissue, expression of both genes occurs predominantly in internodes 4 and 5 (from the apex). MsaCad2, in contrast to MsaCad1, is not significantly expressed in the top three internodes of the stem. Both MsaCad1 and MsaCad2 are wound-inducible, and the wound-responsiveness of each gene is modulated by salicylic acid.
Plant Mol Biol 1999 Sep
PMID:Molecular characterisation and expression of a wound-inducible cDNA encoding a novel cinnamyl-alcohol dehydrogenase enzyme in lucerne (Medicago sativa L.) 1057 94

Although Ca(2+) channel blockers are commonly used to control both blood pressure and angina in patients with coronary artery disease, clinical trials have associated the use of L-type Ca(2+) channel blockers with increased cardiovascular mortality. Recent evidence has implicated Ca(2+) entry through the L-type Ca(2+) channel during transient ischemia as a proximal stimulus for ischemic preconditioning (IPC) in experimental animals. We therefore hypothesized that clinical L-type Ca(2+) channel blockade prevents IPC in human myocardium. Human atrial trabeculae were suspended in organ baths, field simulated at 1 Hz, and force development was recorded. Following 90 min equilibration, trabeculae from control patients and patients taking L-type Ca(2+) channel blockers were subjected to simulated ischemia/reperfusion (I/R: 45/120 min) with or without 5 min of simulated ischemia (IPC stimulus) prior to I/R. IPC increased post-ischemic developed force in control patients from 14.6+/-2.6 to 43.1+/-3.5% baseline developed force (%BDF P<0.05 I/R vs IPC). Whereas IPC failed to increase post-ischemic developed force in myocardium from patients taking L-type Ca(2+) channel blockers (15. 1+/-1.9 vs 16.6+/-1.7 %BDF, P>0.05 L-type I/R v L-type IPC). We conclude that: (1) atrial muscle can be preconditioned by transient ischemia; (2) atrial muscle from patients taking L-type Ca(2+) channel blockers cannot be preconditioned by transient ischemia; and (3) the increased cardiovascular mortality historically associated with the use of Ca(2) channel blockers in patients with coronary artery disease may be, in part, due to the pharmacological inhibition of ischemic preconditioning.
J Mol Cell Cardiol 1999 Dec
PMID:Clinical L-type Ca(2+) channel blockade prevents ischemic preconditioning of human myocardium. 1077 91

Several studies have shown that inflammation plays an important role in the pathogenesis of coronary heart disease (CHD). Serum amyloid A (SAA) and C-reactive protein (CRP) reactants of the acute phase of inflammation, have been shown to be increased in patients with CHD. Recently ex vivo studies demonstrated that some types of atherosclerotic plaques show substantially warmer regions. A catheter-based technique has been developed to measure the temperature of human arteries in vivo. Therefore, the aim of the present study was to measure the luminal surface temperature in patients with CHD and to correlate it with the acute phase proteins in order to discriminate the role of inflammation in heat production in acute coronary syndromes. Sixty patients were studied with CHD (20 with stable angina, 20 with unstable angina and 20 with acute myocardial infarction) and 20 sex- and age-matched controls without coronary artery disease, by measuring plasma levels of SAA, CRP, plasma lipids and intracoronary arterial luminal wall temperature. Intracoronary temperature was measured with a thermography catheter developed in our Institution: a thermistor probe with a temperature accuracy of 0.05 degrees C, was attached at the distal end of a long 3F polyurethane shaft. It was found that the median temperature differences at the site of the lesion from the core temperature was increased in patients with unstable angina (1.025 degrees C) and acute myocardial infarction (2.150 degrees C) compared with stable angina (0.300 degrees C), P<0.001 for each comparison. Furthermore, stable angina has increased temperature differences compared with controls (0.200 degrees C, P<0.001). There were very good correlations between CRP and SAA with the temperature (r=0.796, P=0.01 and r=0.848, P=0.01, respectively). Local heat at the site of lesion is increased in patients with acute coronary syndromes and may arise from an aggressive inflammatory response occurring in these situations. The sensitive measurement of plaque temperature as a prognostic marker may be useful in the management of coronary heart disease.
J Mol Cell Cardiol 2000 Jan
PMID:Heat production of atherosclerotic plaques and inflammation assessed by the acute phase proteins in acute coronary syndromes. 1065 89

Although the Myc family of transcription factors is upregulated in many human tumors, it is unclear which genes are targets for the deregulated Myc. Previous studies suggest that hamster and rat carbamoyl phosphate synthase, aspartate transcarbamylase, dihydroorotase Cad genes are regulated by c-Myc. In fact, of all putative target genes thought to be activated by c-Myc, only the Cad gene showed loss of growth regulation in rat cells nullizygous for c-Myc. However, it was unknown whether upregulation of CAD, which performs the first three rate-limiting steps of pyrimidine biosynthesis, contributes to c-Myc's role in human neoplasia. To explore this possibility, we cloned the human cad promoter. We found that c-Myc could bind to an E box in the human cad promoter in gel shift assays and that growth regulated transcription from the human cad promoter was dependent on this c-Myc binding site. However, the increased amount of c-Myc found in Burkitt's lymphoma cell lines did not lead to increased cad mRNA levels. Thus, we suggest that although c-Myc is clearly important for the normal transcriptional control of the cad promoter, it is unlikely that increased levels of CAD are important mediators of c-Myc-induced neoplasia. Therefore, an understanding of the mechanism by which overexpressed c-Myc contributes to the development of Burkitt's lymphoma requires the identification of additional c-Myc target genes.
Mol Carcinog 2000 Feb
PMID:CAD, a c-Myc target gene, is not deregulated in Burkitt's lymphoma cell lines. 1065 1

The insertion/deletion (I/D) polymorphism of the human angiotensin-converting enzyme (ACE) gene is a major determinant of circulating ACE levels. The D allele has been suggested to be a potent risk factor for coronary artery disease; however, the effect of the ACE gene on carotid atherosclerosis remains controversial. We therefore studied the relationship between the ACE gene I/D polymorphism and carotid artery intima-media thickness (IMT). A random sample of 300 men aged 50-59 years living in southern Finland were selected, and 233 agreed to participate (74%). Data were collected in 219 subjects. Quantitative B-mode ultrasonography was used to measure the maximum near and far wall IMT of right and left common, bifurcation, and internal carotid artery. The mean maximum IMT (overall mean) was calculated as the mean of 12 maximum IMTs at 12 standard sites. Patients with an IMT higher than 1.7 mm in at least one of 12 standard sites were assumed to have carotid atherosclerosis. The I/D polymorphism was determined by polymerase chain reaction. Overestimation of the frequency of the DD genotype was eliminated by insertion-specific primer and the inclusion of 5% dimethylsulfoxide. No significant differences were found in carotid wall thickness between the three genotypes; the overall mean IMT were 1.18 +/- 0.30, 1.22 +/- 0.24, and 1.08 +/- 0.40 mm in genotypes of II, ID, and DD, respectively. Similarly, the ACE genotypes and allele frequencies did not differ significantly between the subjects with and those without carotid atherosclerosis. There was no association in the subgroups among only nonsmoking subjects or subjects without chronic medication. The present data indicate that the I/D polymorphism of the ACE gene is not related to carotid IMT and is unlikely to play a major role in carotid atherosclerosis.
J Mol Med (Berl) 1999 Dec
PMID:Relationship of angiotensin-converting enzyme gene polymorphism to carotid wall thickness in middle-aged men. 1068 21


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