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S Kaufman

Publications and source records attributed to S Kaufman.

At least 217 records · Page 12Linked to original sources
PubMed1989

Immunological studies on the participation of 6-pyruvoyl tetrahydropterin (2'-oxo) reductase, an aldose reductase, in tetrahydrobiopterin biosynthesis.

The NADPH-dependent reduction of the two carbonyl groups in the side chain of the first tetrahydropterin intermediate on the tetrahydrobiopterin biosynthetic pathway, 6-pyruvoyl tetrahydropterin, proceeds in a sequential manner whose order has not yet been resolved. Sepiapterin reductase can catalyze the reduction of both carbonyl groups starting with the 1'-oxo. 6-Pyruvoyl tetrahydropterin (2'-oxo) reductase, which has now been shown to be a member of the aldose reductase family, catalyzes the formation of only the 2'-hydroxy-1'-oxo intermediate which still requires sepiapterin reductase for final conversion to tetrahydrobiopterin. Inhibiting antibodies to the 2'-oxo reductase have been prepared and utilized to explore the distribution of this reductase in rat brain. The antiserum also maximally inhibited in vitro tetrahydrobiopterin synthesis in crude rat brain extracts by 60%, indicating that the majority of tetrahydrobiopterin biosynthesis in vivo may proceed via the 2'-hydroxy-1'-oxo intermediate. However, analogous experiments with rat liver extracts demonstrate that inhibition of the 2'-oxo reductase activity does not inhibit the conversion of 6-pyruvoyl tetrahydropterin to tetrahydrobiopterin, suggesting that tetrahydrobiopterin biosynthesis may proceed via different pathways in rat brain and liver.

Animals↗
PubMed1989

Evidence for the formation of the 4a-carbinolamine during the tyrosine-dependent oxidation of tetrahydrobiopterin by rat liver phenylalanine hydroxylase.

In the presence of phenylalanine and molecular oxygen, activated phenylalanine hydroxylase catalyzes the oxidation of tetrahydrobiopterin. The oxidation of this tetrahydropterin cofactor also proceeds if the substrate, phenylalanine, is replaced by its product, tyrosine, in the initial reaction mixture. These two reactions have been defined as coupled and uncoupled, respectively, because in the former reaction 1 mol of phenylalanine is hydroxylated for every mole of tetrahydrobiopterin oxidized, whereas in the latter reaction there is no net hydroxylation of tyrosine during the oxidation of the tetrahydropterin. During the course of the coupled oxidation of tetrahydrobiopterin, a pterin 4a-carbinolamine intermediate can be detected by ultraviolet spectroscopy (Kaufman, S. (1976) in Iron and Copper Proteins (Yasunobu, K. T., Mower, H. F., and Hayaishi, O., eds) pp. 91-102, Plenum Publishing Corp., New York). Dix and Benkovic (Dix, T. A., and Benkovic, S. J. (1985) Biochemistry 24, 5839-5846) have postulated that the formation of this intermediate only occurs when the oxidation of the tetrahydropteridine is tightly coupled to the concomitant hydroxylation of the aromatic amino acid. However, during the tyrosine-dependent uncoupled oxidation of tetrahydrobiopterin by phenylalanine hydroxylase, we have detected the formation of a spectral intermediate with ultraviolet absorbance that is essentially identical to that of the carbinolamine. Furthermore, this absorbance can be eliminated by the addition of 4a-carbinolamine dehydratase, an enzyme which catalyzes the dehydration of the 4a-carbinolamine. Quantitation of this intermediate suggests that there are two pathways for the tyrosine-dependent uncoupled oxidation of tetrahydrobiopterin by phenylalanine hydroxylase because only about 0.3 mol of the intermediate is formed per mol of the cofactor oxidized.

Animals↗
PubMed1989

The biosynthesis of tetrahydrobiopterin in rat brain. Purification and characterization of 6-pyruvoyl tetrahydropterin (2'-oxo)reductase.

An enzyme with 6-pyruvoyl tetrahydropterin (6PPH4) (2'-oxo)reductase activity was purified to near homogeneity from whole rat brains by a rapid method involving affinity chromatography on Cibacron blue F3Ga-agarose followed by high performance ion exchange chromatography and high performance gel filtration. The enzyme has a single subunit of Mr 37,000 and has a similar amino acid composition to previously described aldoketo reductases. The reductase activity is absolutely dependent on NADPH, will only catalyze the reduction of the C-2'-oxo group of 6PPH4, and is inactive towards the C-1'-oxo group. However, the enzyme also shows high activity towards nonspecific substrates, such as 4-nitrobenzaldehyde, phenanthrenequinone, and menadione. The role of this 6PPH4 reductase in the formation of tetrahydrobiopterin (BH4) was investigated. Measurements were made of the rate of conversion of 6PPH4, generated from dihydroneopterin triphosphate with purified 6PPH4 synthase, to BH4 in the presence of mixtures of pure sepiapterin reductase and the 6PPH4 (2'-oxo)reductase purified from rat brains. The results suggest that when sepiapterin reductase activity is limiting, a large proportion of BH4 synthesis proceeds through the 6-lactoyl intermediate. However, when sepiapterin reductase is not limiting, most of the BH4 is probably formed via reduction of the other mono-reduced intermediate which is produced from 6PPH4 by sepiapterin reductase alone.

Alcohol Oxidoreductases↗
PubMed1989

Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome.

We evaluated cerebrospinal fluid biogenic amine metabolites in 32 patients with Rett syndrome. Significant reductions were noted in the metabolites of norepinephrine, dopamine, and serotonin, as compared with controls of similar age (p less than 0.001, p less than 0.001, and p less than 0.05, respectively). Tetrahydrobiopterin is an essential cofactor and may be rate-limiting for the synthesis of catecholamines and serotonin. Accordingly, total cerebrospinal fluid biopterin was measured and found to be elevated in patients compared with controls (p less than 0.002). These findings constitute the only biochemical changes detected in Rett syndromes so far.

Adolescent↗
PubMed1989

Leukocyte alkaline phosphatase and carcinoembryonic antigen in breast cancer patients: clinical correlation with the markers.

Leukocyte alkaline phosphatase (LAP) scores in peripheral blood and plasma carcinoembryonic antigen (CEA) levels were determined in 208 breast cancer patients with nonmetastatic disease. Patients were followed until clinical manifestations of metastases appeared. Then the LAP score and CEA level were analyzed in relation to the clinical appearance of metastases. Of the 208 patients studied, 58 developed metastases during the follow-up period. The LAP scores and CEA levels of this group of patients were compared to a control group of 60 breast cancer patients who did not develop metastases. Of the two markers, LAP score seems to be considerably more useful in detecting metastatic disease.

Adult↗
PubMed1989

Preoperative adjuvant chemotherapy for advanced head and neck cancer: a surgical evaluation.

This presentation consists of two parts: 1) a brief account of the results of treating 94 patients with stage III (n = 24) and stage IV (n = 70) advanced head and neck cancer, primarily with two courses of preoperative adjuvant chemotherapy; and 2) an evaluation of 42 of the 94 patients consecutively treated by surgery by the senior author. It is our conclusion that preoperative chemotherapy using cisplatin, vincristine, and bleomycin can improve the compromised airway and deglutition without producing deleterious effects relative to surgical complications. Moreover, overall survival is promising and justifies continued study using organized protocols.

Airway Obstruction↗
PubMed1989

Tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylases, is synthesized by and regulates proliferation of erythroid cells.

The only known role for 6(R)-5,6,7,8-tetrahydrobiopterin (BH4) is as the cofactor for the aromatic amino acid hydroxylases. However, BH4 has been shown to be synthesized by cells that do not contain any hydroxylase activity, suggesting that it may have still undiscovered functions. Our finding of much higher levels of BH4 and GTP cyclohydrolase, the first enzyme of de novo BH4 biosynthesis, in rat reticulocytes compared to mature erythrocytes raised the possibility that BH4 might play a role in erythrocyte maturation. We have now demonstrated, by using murine erythroleukemia (MEL) cells as a model for erythrogenesis, that BH4 synthesis is required for proliferation of these cells. Inhibition of BH4 biosynthesis in rapidly dividing MEL cells with N-acetylserotonin, a potent inhibitor of sepiapterin reductase, the terminal enzyme in the BH4 biosynthetic pathway, results in inhibition of DNA synthesis and mitogenesis without induction of hemoglobin synthesis. The inhibition of DNA synthesis is reversed by repletion of cellular BH4 levels with sepiapterin, a pterin that is readily taken up by the cells and converted to BH4 by the sequential reductions of sepiapterin reductase and dihydrofolate reductase. Treatment of MEL cells with hexamethylene bisacetamide, an inducer of differentiation, results in a decrease in BH4 synthesis accompanied by a cessation of growth and concomitant hemoglobin synthesis. The inhibition of proliferation induced by hexamethylene bisacetamide can be reversed by maintaining high intracellular levels of BH4, which also decreases the amount of hemoglobin. The mechanism of the BH4 effect has not yet been elucidated, but it appears as though BH4 synthesis is more intimately linked with cell proliferation than with the differentiation process.

Acetamides↗
PubMed1989

Clinical manifestations and laboratory findings in patients with lupus anticoagulants.

Clinical and laboratory features were evaluated in 48 patients with lupus anticoagulants and the efficiency of three different assays in the detection of lupus anticoagulants was compared. The diagnosis of lupus anticoagulants was based on a prolonged activated partial thromboplastin test not corrected in a mixture of 1:1 with normal plasma and lack of specific inhibitors against coagulation factors. Platelet neutralization procedure was positive for lupus anticoagulants in 98% of the patients, tissue thromboplastin inhibition ratio in 79%, and kaolin clotting time index in 77%. At least one of the assays was positive in 100% of the cases. The largest minority of the patients (31%) suffered from systemic lupus erythematosus. The others had a variety of non-immunological disorders. In the 13 patients who had been operated on, only 1 with renal failure developed hemorrhagic complications after renal biopsy due to thrombocytopathy. The incidence of recurrent spontaneous miscarriage, immune thrombocytopenia and positive direct antiglobulin test, anti-nuclear and anti-DNA antibodies and VDRL was significantly higher in patients with lupus anticoagulants and systemic lupus erythematosus compared to patients with lupus anticoagulants but without systemic lupus erythematosus.

Autoantibodies↗
PubMed1989

Folic acid deficiency, megaloblastic anemia and peripheral polyneuropathy due to oral contraceptives.

A 34-year-old woman developed megaloblastic anemia and peripheral polyneuropathy following the use of oral contraceptives for 4 years. Low levels of folic acid and vitamin B12 were found. Both the complete recovery after therapy with the vitamins, and the absence of other causes of vitamin B12 and folate deficiency, suggest that the vitamin deficiencies were caused by the oral contraceptives and resulted in the rare combination of megaloblastic anemia and polyneuropathy. The poor response to vitamin B12 alone, and the development of anemia and polyneuropathy 4 months after cessation of vitamin B12 therapy suggest that folate deficiency was the primary problem.

Adult↗
PubMed1989

Neopterin: a predictive marker of acquired immune deficiency syndrome in human immunodeficiency virus infection.

In 79 homosexual men infected with human immunodeficiency virus (HIV), urinary neopterin was significantly higher as compared with 70 HIV-seronegative men in the same cohort (p less than 0.0001). This highly significant association was found both for naturally occurring oxidized (native) neopterin and for total neopterin (native plus chemically oxidized forms). In prospective follow-up for 18 months, the odds that the acquired immune deficiency syndrome (AIDS) would develop were elevated 25-fold among those whose native neopterin levels were in the highest quartile compared with those with lower neopterin levels, and the corresponding odds ratio for total neopterin was 7.8. Logistic regression analyses indicated that neopterin added useful information to T4-cell count in predicting AIDS onset and that both are statistically significant in the multivariate model. A cross-sectional survey revealed that neopterin levels were correlated with number of receptive anal intercourse partners in the year before HIV seroconversion (r = 0.60, p = 0.0005). Since neopterin may serve as a marker of monocyte/macrophage activation by soluble factors such as gamma-interferon, these data support a growing body of virologic and immunologic evidence that highlights the important role of the monocyte/macrophage in the pathogenesis of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Urinary neopterin concentrations vs total neopterins for clinical utility.

Neopterin measurements are especially useful as an early marker in (e.g.) allograft rejections and in patients infected with human immunodeficiency virus type 1 (HIV-1). An increased concentration of total neopterins (neopterin + dihydroneopterin) is also a significant marker in patients with HIV-1 infection. In this study we compared concentrations of neopterin and total neopterins in urine samples from 77 homosexual men with and 73 without established HIV-1 infection. HIV-1-seropositive homosexual men had higher concentrations of neopterin and total neopterins (and 7,8-dihydroneopterin) in their urine than did those who were HIV-1-seronegative, and there was a close correlation between neopterin and total neopterins. Both neopterin variables correlated inversely with CD4+ T-cell counts and CD4+/CD8+ T-cell ratios but not with CD8+ T-cell counts in the HIV-1-seropositive men. Our data indicate that measurements of neopterin and total neopterins are of almost equal potential for clinical diagnosis. However, when measuring total neopterins, which includes oxidation of 7,8-dihydroneopterin to neopterin, more strict requirements of sample collection and handling are necessary to avoid degradation of the 7,8-dihydro derivative.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Nutritional impact of acquired immune deficiency syndrome: a unique counseling opportunity.

The acquired immune deficiency syndrome (AIDS) presents a challenge for dietitians. Changes in the immune system have a potentially detrimental effect on nutritional status as a result of conditions such as anorexia, infection, diarrhea, and drug side effects. Conversely, poor nutrition status may adversely alter the immune systems. Dietary guidelines for the management of these conditions and additional obstacles are discussed. When counseling patients with AIDS, the dietitian needs to be aware of and sensitive to alternative therapies, to evaluate their effectiveness, and to assist in determining their place in the patient's treatment. Psychosocial factors that could influence nutritional status, such as dementia, unemployment, and isolation, must also be taken into consideration. A nutrition program has been established to address the needs of AIDS patients at AIDS Project Los Angeles-Necessities of Life Program (APLA-NOLP), a food distribution center. The goal of the program is to maintain or improve the client's nutritional status by providing education and counseling. The nutrition program has been enthusiastically received, and the outcome of the program on the nutritional status of the participants is currently under study. The dietitian is in a unique position to intervene by providing resource information, food preparation tips, and individualized nutrition plans. It is imperative that the dietitian become familiar with the AIDS disease process and its implications for nutritional status to be considered an expert in the nutrition management of such patients.

Acquired Immunodeficiency Syndrome↗
PubMed1988

The tyrosine-dependent oxidation of tetrahydropterins by lysolecithin-activated rat liver phenylalanine hydroxylase.

In the presence of tyrosine, phenylalanine hydroxylase, which has been activated with lysolecithin, catalyzes the oxidation of tetrahydrobiopterin at a rate 10-20% that of the parallel reaction with phenylalanine. Unlike the reaction with phenylalanine, there is no net concomitant hydroxylation of tyrosine, although the amino acid is still a necessary component. Tyrosine appears to form an abortive complex with the activated enzyme, the pterin cofactor and molecular oxygen. The Km for tetrahydrobiopterin is identical for the reactions with phenylalanine and tyrosine, whereas the Km for tyrosine is approximately 3 1/2 times greater than the Km for phenylalanine. The tyrosine-dependent oxidation of tetrahydrobiopterin proceeds at both pH 6.8 and 8.2 and shows a similar dependence on the pH as that of the physiological reaction. Tetrahydrobiopterin can be replaced by the artificial cofactor, 6-methyltetrahydropterin, in the tyrosine-dependent oxidation at both pH 6.8 and 8.2. As in the parallel reaction with phenylalanine, both the Km for the cofactor and the Km for the aromatic amino acid increase with this substitution.

Animals↗
PubMed1988

The auto-oxidation of tetrahydrobiopterin.

The product of the aerobic oxidation of tetrahydrobiopterin, quinonoid dihydrobiopterin, is unstable and rapidly rearranges to form a 7,8-dihydropteridine. Kaufman [Kaufman, S. (1967) J. Biol. Chem. 242, 3934-3943] identified the stable product produced in 0.1 M phosphate pH 6.8, as 7,8-dihydrobiopterin. However, Armarego et al. [Armarego, W. L. F., Randles, D. and Taguchi, H. (1983) Eur. J. Biochem. 135 393-403] questioned this assignment because they found that the dihydroxypropyl group on C-6 was eliminated and 7,8-dihydropterin was the predominant product when the aerobic oxidation was performed in 0.1 M Tris pH 7.6. In the present study we demonstrate that the rearrangement of the unstable quinonoid dihydrobiopterin results in a mixture of these two 7,8-dihydropteridines at neutral pH, 25 degrees C. Furthermore, we find that the loss or retention of the alkyl side-chain is not solely dependent on the pH of the reaction mixture, as was previously assumed by Armarego et al., but rather is strongly influenced by the temperature and the type of buffer. In addition, we describe a new method for quantifying the relative amounts of these two 7,8-dihydropteridines in mixtures of unknown concentrations. This method relies on multicomponent analysis of second derivative spectra and results in values which agree with the concentrations determined directly by HPLC.

Air↗
PubMed1988

Characterization of the human granulocyte-macrophage colony-stimulating factor receptor.

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine derived from activated T cells, endothelial cells, fibroblasts, and macrophages. It stimulates myeloid and erythroid progenitors to form colonies in semisolid medium in vitro, as well as enhancing multiple differentiated functions of mature neutrophils, macrophages, and eosinophils. We have examined the binding of human GM-CSF to a variety of responsive human cells and cell lines. The most mature myelomonocytic cells, specifically human neutrophils, macrophages, and eosinophils, express the highest numbers of a single class of high affinity receptors (Kd approximately 37 pM, 293-1000 sites/cell). HL-60 and KG-1 cells exhibit an increase in specific binding at high concentrations of GM-CSF; computer analysis of the data is nonetheless consistent with a single class of high affinity binding sites with a Kd approximately 43 pM and 20-450 sites/cell. Dimethyl sulfoxide induces a 3-10-fold increase in high affinity receptors expressed in HL-60 cells, coincident with terminal neutrophilic differentiation. Finally, binding of 125I-GM-CSF to fresh peripheral blood cells from six patients with chronic myelogenous leukemia was analyzed. In three of six cases, binding was similar to the nonsaturable binding observed with HL-60 and KG-1 cells. GM-CSF binding was low, or in some cases, undetectable on myeloblasts obtained from eight patients with acute myelogenous leukemia. The observed affinities of the receptor for GM-CSF are consistent with all known biological activities. Affinity labeling of both normal neutrophils and dimethyl sulfoxide-induced HL-60 cells with unglycosylated 125I-GM-CSF yielded a band of 98 kDa, implying a molecular weight of approximately 84,000 for the human GM-CSF receptor.

Affinity Labels↗