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Biomedical subjects

S Kaufman

Publications and source records attributed to S Kaufman.

At least 199 records · Page 11Linked to original sources
PubMed1991

Studies on the partially uncoupled oxidation of tetrahydropterins by phenylalanine hydroxylase.

The uncoupled portion of the partially uncoupled oxidation of tetrahydropterins by phenylalanine hydroxylase can be described by the same model as we have recently derived for the fully uncoupled reaction (Davis, M.D. and Kaufman, S. (1989) J. Biol. Chem. 264, 8585-8596). Although essentially no hydrogen peroxide is formed during the fully coupled oxidation of tetrahydrobiopterin or 6-methyltetrahydropterin by phenylalanine hydroxylase when phenylalanine is the amino acid substrate, significant amounts of hydrogen peroxide are formed during the partially uncoupled oxidation of 6-methyltetrahydropterin when para-fluorophenylalanine or para-chlorophenylalanine are used in place of phenylalanine. Similarly, during the partially uncoupled oxidation of the unsubstituted pterin, tetrahydropterin, even in the presence of phenylalanine, hydrogen peroxide formation is detected. The 4a-carbinolamine tetrahydropterin intermediate has been observed during the fully uncoupled tyrosine-dependent oxidations of tetrahydropterin and 6-methyltetrahydropterin by lysolecithin-activated phenylalanine hydroxylase, suggesting that this species is also a common intermediate for uncoupled oxidations by this enzyme.

Animals↗
PubMed1991

Some metabolic relationships between biopterin and folate: implications for the "methyl trap hypothesis".

Tetrahydrobiopterin and the folate coenzymes can reciprocally interact in ways that would be useful to the metabolic pathways subserved by both of these coenzymes. Thus, through one of the reactions catalyzed by methylene tetrahydrofolate reductase, 5-CH3-H4-folate can regenerate BH4 from q-BH2 and q-BH2 can provide an escape from the "methyl trap."

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1991

Cerebrospinal fluid and serum neopterin and biopterin in D-retrovirus-infected rhesus macaques (Macaca mulatta): relationship to clinical and viral status.

Increases in serum and cerebrospinal fluid (CSF) neopterin concentrations accompany many inflammatory diseases, including infection with HIV-1 and may reflect activation of guanosine triphosphate (GTP) cyclohydrolase 1 by gamma-interferon and other cytokines. In the present study, macaques with clinical simian AIDS (SAIDS) infected with the immunosuppressive type-D retrovirus D/1/California had increased concentrations of CSF neopterin but not of biopterin beginning soon after seroconversion. Normal neopterin concentrations in the CSF were found in macaques with SAIDS-related complex as well as asymptomatic, viremic macaques. CSF biopterin, serum neopterin and serum biopterin concentrations of D/1/California-infected macaques were not different from the levels in control animals. The increase in CSF neopterin may reflect local inflammatory responses and paralleled previously documented changes in L-tryptophan metabolism in these macaques. However, the absence of macrophage infiltrates in the brain of the infected macaques suggests a non-macrophage source of both increased CSF neopterin and tryptophan metabolites in the SAIDS macaques.

Animals↗
PubMed1991

Effects of pregnancy, estradiol, and progesterone on pressor responsiveness to angiotensin II.

The pressor and heart rate responses to infused angiotensin (ANG) II were measured in conscious pregnant Long-Evans rats. Responses were recorded 7 days after chronic indwelling venous and arterial cannulas were implanted (virgin rats) and again at days 7, 14, and 21 of pregnancy. A significant reduction in the pressor response was noted as early as day 7 of pregnancy; this is comparable to the human condition. It was also noted that the reflex bradycardia associated with the pressor response was entirely absent at 21 days. To determine a possible cause of these pregnancy-induced changes, ovariectomized rats were injected subcutaneously for 10 days with estradiol, progesterone, or a combination of both. They were then tested for pressor responses to ANG II. None of the hormone-injected groups showed any significant deviation in their pressor response compared with saline-injected controls. Similar results were obtained in acutely prepared rats under chloroform anesthesia. However, the magnitude of the pressor response in the chloroformed animals was significantly reduced compared with the conscious unrestrained animals. It is concluded that 1) the rat is an appropriate model of human pregnancy in which to study changes in ANG responsiveness in pregnancy and 2) neither estradiol nor progesterone is responsible for the reduced pressor response.

Angiotensin II↗
PubMed1991

Leukocyte alkaline phosphatase and carcinoembryonic antigen in colorectal cancer patients (usefulness in the assessment of the stage).

Leukocyte alkaline phosphatase (LAP) scores in peripheral blood, and plasma carcinoembryonic antigen (CEA) levels were determined in 122 colorectal cancer patients, and compared to 30 healthy persons, who served as controls. Both markers are gradually elevated according to the severity of tumor penetration. LAP scores in Dukes'C and D (157 +/- 79) were significantly higher than in Dukes'A, B1 and B2 (81 +/- 43), p less than 0.001. CEA levels were also higher in Dukes'C and D (50 +/- 95) than in patients with Dukes'A, B1 and B2 (25 +/- 54), p less than 0.07, but less significantly. The LAP score has at least the same reliability as the CEA values as a marker of stage in colorectal cancer patients.

Alkaline Phosphatase↗
PubMed1991

Dihydropteridine reductase activity: lack of association with serum aluminum levels and cognitive functioning in patients with end-stage renal disease.

Although increased levels of aluminum (Al) are present in patients with dialysis encephalopathy (DE), it is unclear if the association is causal. The enzyme dihydropteridine reductase (DHPR) plays a critical role in neurotransmitter formation and its activity. Elevated levels of Al are reported to decrease DHPR activity, which would alter neurotransmitter metabolism, thus producing DE. We examined the association between erythrocyte DHPR activity and Al levels, attention/psychomotor skills, and depression in a group of 21 patients with end-stage renal disease. DHPR activity was not related to Al level, mental status, psychomotor ability, or depression score. After administration of deferoxamine (an Al chelating agent), Al level increased significantly but DHPR activity remained the same. Our results suggest that the mechanism for the development for DE does not involve alterations of neurotransmitter metabolism caused by Al-mediated reductions in DHPR activity.

Adult↗
PubMed1990

Studies on the interaction of a thiol-dependent hydrogen peroxide scavenging enzyme and phenylalanine hydroxylase.

Rat liver phenylalanine hydroxylase is irreversibly inactivated by a H2O2-dependent process. Since H2O2 can be produced by autooxidation of the tetrahydropterin cofactor required for the hydroxylation reaction, in vitro assays are usually carried out in the presence of added catalase. On the basis of a dithiothreitol-dependent protecting assay of phenylalanine hydroxylase, carried out in the absence of catalase, we have isolated an enzyme fraction from neonatal rat livers which has similar properties to the known enzyme, glutathione peroxidase. The developmental time course for phenylalanine hydroxylase in rats has been reported to follow two different patterns. Using the dithiothreitol assay, McGee et al. (1972, Biochem. J. 127, 669-674) have found that newborn rats have low phenylalanine hydroxylase activity which increases to adult levels over several months. On the other hand, using catalase-supplemented assays, others have found that newborn rats have nearly adult levels of phenylalanine hydroxylase activity. The protective effect of glutathione peroxidase on phenylalanine hydroxylase suggests that the developmental time course found by McGee et al. may represent the slow developmental time course previously found for glutathione peroxidase. In addition, feeding rats a selenium-deficient diet, which reduces the hepatic activity of the selenium-containing glutathione peroxidase, results in a concomitant irreversible loss of phenylalanine hydroxylase activity, suggesting that glutathione peroxidase may play a vital role in protecting phenylalanine hydroxylase in vivo from peroxide inactivation.

Animals↗
PubMed1990

Tuftsin induces tissue factor-like activity in human mononuclear cells and in monocytic cell lines.

Normal human monocytes and macrophages generate potent procoagulant activity (PCA) resembling tissue factor (TF) in response to various stimuli. In this study we show that tuftsin, a natural stimulator of many functions of monocytes and macrophages, also stimulates a potent PCA in mixed mononuclear cells and monocytes, and a mild PCA in lymphocytes and cell lines of monocytic origin (U937 and THP). No activity was generated by several lymphoid cell lines and HL-60 cells. The PCA resembled TF in that it accelerated clotting through the extrinsic coagulation pathway and was inhibited by concanavalin-A and by monoclonal anti-TF antibodies. The induction of TF-like activity by tuftsin was dose- and time-dependent. It was located in the cell membrane and did not require T cells for expression. Generation of TF-like activity was prevented by actinomycin D, while cytarabine had no effect on this process, suggesting that expression of the activity depends on protein synthesis. Studies with various tuftsin analogs suggest that tuftsin stimulates generation of TF-like activity, as well as other functions of monocytes via the same receptors. The results with the monocytic cell lines show that tuftsin affects mainly mature cells. The induction of TF-like activity in mononuclear cells by tuftsin constitutes an important link between mononuclear cells and the immune and coagulation systems. It may play a major role in the pathogenesis of thromboembolism and fibrin deposition in various inflammatory and immunologic disorders.

Blood Coagulation Factors↗
PubMed1990

Dependence of an alkyl glycol-ether monooxygenase activity upon tetrahydropterins.

Glyceryl-ether monooxygenase (1-alkyl-sn-glycerol,tetrahydropteridine: oxygen oxidoreductase, EC 1.14.16.5) catalyzes the oxidative cleavage of 1-O-alkyl glycerol or glycol derivatives to a long-chain aldehyde and the glycerol or glycol derivative. The specificity for tetrahydropterins of a similar, perhaps identical, enzyme that cleaves O-hexadecyl ethylene glycol in rat liver microsomes was examined with the use of an assay based on [1-3H]ethylene glycol formation from 2-hexadecyloxy [1-3H]ethan-1-ol. Several tetrahydropterin derivatives are effective electron donors for this reaction, and 2,4,5-triamino-6-hydroxypyrimidine is somewhat effective, but NADH, NADPH, ascorbate, reduced dichlorophenolindophenol and glutathione are inactive. Tetrahydropterin derivatives differ from each other in apparent Km and apparent Vmax. The order of increasing apparent Km values is tetrahydropterin approximately 6-methyltetrahydropterin approximately tetrahydrobiopterin less than 6.7-dimethyltetrahydropterin less than tetrahydrofolate. The order of increasing apparent Vmax values is tetrahydrofolate approximately tetrahydropterin less than 6-methyltetrahydropterin approximately tetrahydrobiopterin approximately 6,7-dimethyltetrahydropterin. Results obtained with the use of a spectrophotometric assay, in which tetrahydropterin oxidation is coupled to NADH oxidation by dihydropteridine reductase (NAD(P)H: 6,7-dihydropteridine oxidoreductase, EC 1.6.99.7), indicated that the ratio of 6,7-dimethyltetrahydropterin or 6-methyltetrahydropterin oxidized to ether lipid degraded is about 1.1 to 1.3. Unlike cytochrome P-450-dependent hydroxylases, this alkyl glycol-ether monooxygenase is not inhibited by carbon monoxide. 1-O-hexadecyl-rac-glycerol (chimyl alcohol) competitively inhibits the oxidation of the glycol ether indicating that the same enzyme probably catalyzes the oxidation of both O-alkyl glycol and 1-O-alkyl glycerol.

Alcohols↗
PubMed1990

The development and function of gamma delta T cells.

In June of this year, a small group of researchers came together at the inspiring location of Segovia, Spain to exchange information and opinions on gamma delta T cells. In this report the new, unpublished findings presented, and the ideas that germinated during the meeting are discussed in the context of recent gamma delta literature.

Animals↗
PubMed1990

Isolation and expression of rat liver sepiapterin reductase cDNA.

Sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase, EC 1.1.1.153) catalyzes the terminal step in the biosynthetic pathway for tetrahydrobiopterin, the cofactor necessary for aromatic amino acid hydroxylation. We report here the isolation of a cDNA clone for rat liver sepiapterin reductase. The cDNA has been excised from a lambda vector and the DNA sequence was determined. The insert contains the coding sequence for at least 95% of the rat enzyme and is fused to the Escherichia coli beta-galactosidase N-terminal segment and the lac promoter. The N-terminal region of the clone contains an extraordinarily high G + C content. The amino acid sequence deduced from the clone is in agreement with the size and composition of the enzyme and was matched to several tryptic peptide sequences. The enzyme encoded by the cDNA insert was shown to have sepiapterin reductase activity after expression in E. coli. Structural similarities were identified between this protein and several enzymes that should contain similar nucleotide and pteridine binding sites.

Alcohol Oxidoreductases↗
PubMed1990

Recurrent acute renal failure complicating IgG warm-type autoimmune intravascular haemolysis.

A 44-year-old woman experienced recurrent episodes of massive intravascular haemolysis complicated by acute oliguric renal failure over a period of 22 years. The haemolysis was induced by IgG warm type autoantibody and complement and responded to corticosteroid therapy. The renal failure was treated effectively by dialysis. To our knowledge, such a life long occurrence of recurrent intravascular haemolysis induced by IgG warm type autoantibodies together with renal failure has not been reported before.

Acute Kidney Injury↗
PubMed1990

Immunological evidence for the requirement of sepiapterin reductase for tetrahydrobiopterin biosynthesis in brain.

Specific antibodies to sepiapterin reductase were used to investigate its involvement in de novo (6R)-5,6,7,8-tetrahydrobiopterin (BH4) biosynthesis in rat brain. Antisepiapterin reductase (anti-SR) serum totally inhibited NADPH-dependent sepiapterin reductase activity in supernatants from discrete rat brain areas and liver. The anti-SR serum also inhibited the conversion of 7,8-dihydroneopterin triphosphate to BH4 in rat brain extracts. The inhibition was accompanied by a concentration-dependent increase in the formation of 6-lactoyltetrahydropterin (6LPH4), a proposed intermediate in BH4 biosynthesis. In addition, anti-SR serum was used to characterize the distribution and molecular properties of sepiapterin reductase in rat tissues. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by Western blotting indicated that there was a single polypeptide with the same molecular weight (28,000) as that of the subunit of pure sepiapterin reductase present in all tissues examined except for liver, where an immunoreactive protein of higher molecular weight (30,500) also was detected. Two-dimensional gel electrophoresis of rat striatum and liver demonstrated that the isoelectric point of sepiapterin reductase from both tissues was 6.16 and that the higher molecular weight immunoreactive material in liver had an isoelectric point of 7.06. Our studies with specific anti-SR serum confirmed the results of previous studies using chemical inhibitors of sepiapterin reductase, which suggested that sepiapterin reductase activity was essential for BH4 biosynthesis in the CNS and that 6LPH4 could be a precursor of BH4.

Alcohol Oxidoreductases↗
PubMed1990

Renal and hormonal responses to prolonged atrial stretch.

The relationship between prolonged (6 h) atrial stretch, urine output, and plasma atrial natriuretic factor (ANF) was investigated in conscious rats. On inflation of a balloon at the superior venal caval-right atrial junction, urine volume and sodium output increased. However, this renal response was no longer apparent after the first hour, and there were no further changes in urine output when the balloon was deflated. This transient renal response was most marked during the first 30 min of balloon inflation, at which time plasma ANF was also elevated. At 6 h, plasma ANF was still elevated, although urine output had, by then, returned to normal. On deflation of the balloon, plasma ANF levels returned to normal. It is clear that the renal and hormonal responses to atrial stretch may be temporally uncoupled. This probably reflects adaptation of the atrial volume receptors in the absence of such an effect on ANF release. Although this might be interpreted to mean that ANF is not of physiological importance in fluid and electrolyte balance, a more plausible explanation is that ANF needs the backing of the reflex pathways arising from stimulation of the atrial receptors to express its natriuretic activity.

Animals↗
PubMed1990

Leukocyte alkaline phosphatase and carcinoembryonic antigen in breast cancer patients. Influence of the treatment on the markers.

Leukocyte alkaline phosphatase (LAP) scores and carcinoembryonic antigen (CEA) levels were analyzed in 53 patients suffering from breast cancer. All patients underwent mastectomy and received adjuvant treatment, and all lived more than 5 years after diagnosis without metastatic disease. Thirty-three patients received adjuvant radiotherapy, and 20 patients received adjuvant chemotherapy. The median LAP score before radiotherapy was 117 +/- 48; two months after the beginning of radiotherapy this value was 175 +/- 71, being significantly higher than the original value (p less than 0.001), and one year after the beginning of radiotherapy it was 105 +/- 63, which approximated the normal scores. The median LAP score before chemotherapy was 138 +/- 69; two months after the beginning of chemotherapy it was 194 +/- 63, i.e. significantly higher than before chemotherapy (p less than 0.002), and one year after the beginning of chemotherapy it was 150 +/- 56. Median CEA levels before radiotherapy were 6.4 +/- 5.1 ng/ml; two months after the beginning of radiotherapy this value was 6.0 +/- 5.0 ng/ml; and one year later 7.4 +/- 6.2 ng/ml. Median CEA levels before chemotherapy were 8.1 +/- 12.0 ng/ml; two months after the beginning of chemotherapy 12.6 +/- 13.0 ng/ml (p less than 0.05) in comparison with the values before chemotherapy; and one year after the beginning of chemotherapy it was 8.6 +/- 5.4 ng/ml. We concluded that the LAP scores were influenced by adjuvant radio- or chemotherapy, and the CEA levels were influenced by chemotherapy.

Alkaline Phosphatase↗