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PubMed1979

Accumulation of a tetrahydroisoquinoline in phenylketonuria.

3',4'-Deoxynorlaudanosolinecarboxylic acid (DNLCA), a tetrahydroisoquinoline derived from dopamine and phenylpyruvic acid, has been detected by computerized mass fragmentography in urine of phenylketonuric children and in urine and brain of rats with experimentally induced hyperphenylalaninemia. Levels of DNLCA in brain of treated animals were more than tenfold higher than controls, and the excess tetrahydroisoquinoline appeared to accumulate in the cerebellum and cortex. DNLCA is a noncompetitive inhibitor of dopamine beta-hydroxylase (inhibition constant, Ki, = 0.42 mM) and is taken up by the brain.

Adolescent↗
PubMed1978

Amino acid and protein metabolism in renal failure.

There are many cAUSES OF ALTERED AMINO ACID AND PROTEIN METABOLISM IN UREMIA WHICH MAY Lead to impaired growth, wasting, malnutrition, and other aspects of the uremic syndrome. These causes have complex interrelationships that are not well understood. The factors include altered nutrition due to poor intake, losses of nutrients during dialysis, and abnormal metabolism of many nutrients. Uremic toxins, superimposed catabolic illnesses, elevated or reduced serum hormone levels, reduced capacity of the kidney to synthesize certain amino acids and to degrade other amino acids, peptides, and small proteins, and decreased excretion of certain amino acids and peptides may also contribute to altered amino acid and protein metabolism. The response of certain plasma amino acids to protein restriction appears to differ in uremic patients as compared to normal subjects. Increased plasma levels of many products of amino acids and proteins in renal failure are due primarily to decreased urinary clearance by the kidney. However, for some metabolites, increased synthesis or decreased degradation may also contribute to elevated levels. These latter compounds include guanidinosuccinic acid, methylguanidine, certain middle molecules, and in some patients, phenylpyruvic acid.

Amino Acids↗
PubMed1999

Production of tyrosine and other aromatic compounds from phenylalanine by rumen microorganisms.

Rumen contents from three fistulated Japanese native goats fed Lucerne hay cubes (Medicago sativa) and concentrate mixture were collected to prepare the suspensions of mixed rumen bacteria (B), mixed protozoa (P) and a combination of the two (BP). Microbial suspensions were anaerobically incubated at 39 degrees C for 12 h with or without 1 mM of L-phenylalanine (Phe). Phe, tyrosine (Tyr) and other related compounds in both supernatant and microbial hydrolysates of the incubations were analyzed by HPLC. Tyr can be produced from Phe not only by rumen bacteria but also by rumen protozoa. The production of Tyr during 12 h incubation in B (183.6 mumol/g MN) was 4.3 times higher than that in P. One of the intermediate products between Phe and Tyr seems to be p-hydroxyphenylacetic acid. The rate of the net degradation of Phe incubation in B (76.0 mumol/g MN/h) was 2.4 times higher than in P. In the case of all rumen microorganisms, degraded Phe was mainly (> 53%) converted into phenylacetic acid. The production of benzoic acid was higher in P than in B suspensions. Small amount of phenylpyruvic acid was produced from Phe by both rumen bacteria and protozoa, but phenylpropionic acid and phenyllactic acid were produced only by rumen bacteria.

Amino Acids↗
PubMed1990

High-performance liquid chromatographic analysis of alpha-keto acids produced from amino acid metabolism in oral Bacteroides.

Profiles of metabolic alpha-keto acids were determined by a high-performance liquid chromatographic method and applied to characterization of oral black-pigmented Bacteroides. Each bacterial strain was incubated with amino acids in a chemically defined medium. After production alpha-keto acids were purified by hydrazide gel column treatment and converted to u.v.-absorbing derivatives. They were analysed by reversed-phase ion-pair chromatography. Black-pigmented Bacteroides species were differentiated into two groups according to production of aromatic alpha-keto acids. Bacteroides gingivalis, B. endodontalis and B. loescheii produced both p-hydroxyphenylpyruvic and phenylpyruvic acids. However, no such alpha-keto acids were produced by B. levii, B. intermedius and B. denticola. In addition, production profiles of several aliphatic alpha-keto acids (alpha-ketoglutaric, pyruvic, alpha-ketobutyric, alpha-ketoisovaleric, alpha-ketoisocaproic, and alpha-keto-beta-methylvaleric acids) separated each individual species in such groups. The present study offers useful chemotaxonomic information on amino acid metabolic activity of oral black-pigmented Bacteroides species.

Amino Acids↗
PubMed1985

Determination of alpha-keto acids in serum and urine by high-performance liquid chromatography with fluorescence detection.

A simple, rapid and highly sensitive high-performance liquid chromatographic method for the determination of alpha-keto acids in serum and urine is described. In dilute hydrochloric acid, alpha-keto acids are converted by 1,2-diamino-4,5-dimethoxybenzene into highly fluorescent quinoxalinone derivatives. The derivatives are isocratically separated simultaneously within 14 min by reversed-phase chromatography on a Radial-Pak cartridge C18 and detected fluorimetrically. The limits of detection are 10-300 fmol in an injection volume of 10 microliters (40-1200 pmol/ml of serum or urine). This sensitivity permits precise determination of several alpha-keto acids in 5 microliter of serum or urine from healthy persons, and also the determination of phenylpyruvic acid in normal urine which cannot be simultaneously determined by other methods.

Adult↗
PubMed1986

Blood-brain barrier transport of the alpha-keto acid analogs of amino acids.

A number of alpha-keto acid analogs of amino acids have been found to penetrate the blood-brain barrier (BBB). Pyruvate, alpha-ketobutyrate, alpha-ketoisocaproate, and alpha-keto-gamma-methiolbutyrate all cross the BBB by a carrier-mediated process and by simple diffusion. Under normal physiological conditions, diffusion accounts for roughly 15% or less of total transport. Aromatic alpha-keto acids, phenylpyruvate, and p-hydroxyphenylpyruvate do not penetrate the BBB, nor do they inhibit the transport of other alpha-keto acids. Evidence based primarily on inhibition studies indicates that the carrier-mediated transport of alpha-keto acids occurs via the same carrier demonstrated previously for propionate, acetoacetate, and beta-hydroxybutyrate transport, commonly referred to as the monocarboxylate carrier. As a group, the alpha-keto acid analogs of the amino acids have the highest affinity for the carrier, followed by propionate and beta-hydroxybutyrate. Starvation for 4 days induces transport of alpha-keto acids, but transport is suppressed in rats fed commercial laboratory rations and subjected to portacaval shunts. The mitochondrial pyruvate translocator inhibitor alpha-cyanocinnamate has no effect on the BBB transport of alpha-keto acids.

3-Hydroxybutyric Acid↗
PubMedDate not supplied

[Disorders of phenylalanine and tyrosine metabolism in Down's syndrome].

Content of phenylalanine and tyrosine was increased in blood serum in mongolism. When 4 patients with mongolism and 10 healthy persons were loaded with 1-phenylalanine, content of the amino acid in blood serum of patients exceeded 1.5--2-fold that found in healthy persons within 4 and 6 hrs after the treatment. The hydroxylation rate of phenylalanine was lower in mongolism as compared to normal state; it corresponded to the rate of phenylalanine hydroxylation in atypical homo- and heterozygote patients bearing "phenylketonuria" gene and in patients with viral hepatitis. Concentration of tyrosine was distinctly higher in the impaired patients within 2--6 hrs after the loading as compared with the healthy persons. But content of tyrosine was increased only slightly in patients with mongolism during the loading and excretion of homogentisinic acid with urine was decreased. These data suggest that activity of phenylalanine hydroxylase system is impaired in liver tissue in mongolism. Excretion of phenylpyruvic acid with urine was not observed in the patients and healthy persons both before and during the amino acid loading. The data obtained suggest that impairment of phenylalanine and tyrosine turnover in mongolism appears to be one of the factors responsible for disturbance of neurotransmitter synthesis and to be related to development of mental retardation.

Adolescent↗
PubMed1987

The reduction of aromatic alpha-keto acids by cytoplasmic malate dehydrogenase and lactate dehydrogenase.

This study demonstrates that cytoplasmic malate dehydrogenase (MDH-s) catalyzes the reduction of aromatic alpha-keto acids in the presence of NADH, that the enzyme which has been described in the literature as aromatic alpha-keto acid reductase (KAR; EC 1.1.1.96) is identical to MDH-s, and that the reduction of aromatic alpha-keto acids is due predominantly to a previously unrecognized secondary activity of MDH-s and the remainder is due to the previously recognized activity of lactate dehydrogenase (LDH) toward aromatic keto-acids. MDH-s and KAR have the same molecular weight, subunit structure, and tissue distribution. Starch gel electrophoresis followed by histochemical staining using either p-hydroxy-phenylpyruvic acid (HPPA) or malate as the substrate shows that KAR activity comigrates with MDH-s in all species studied except some marine species. Inhibition with malate, the end product of the MDH reaction, substantially reduces or totally eliminates KAR activity. Genetically determined electrophoretic variants of MDH-s seen in the fresh water bony fish of the genus Xiphophorus and the amphibian Rana pipiens exhibited identical variation for KAR, and the two traits cosegregated in the offspring from one R. pipiens heterozygote studied. Both enzymes comigrate with no electrophoretic variation among several inbred strains of mice. Antisera raised against purified chicken MDH-s totally inhibited both MDH-s and KAR activity in chicken liver homogenates. There is no evidence to suggest that any protein besides MDH-s and LDH catalyzes this reaction with the possible exception of the situation in Xiphophorus, in which a third independent zone of HPPA reduction is observed. In most species the activity formerly described as KAR appears to be due to a previously unsuspected activity of MDH-s toward aromatic monocarboxylic alpha-keto acids. In all species examined the KAR activity is associated only with MDH-s; in tissue homogenates the mitochondrial form of MDH (MDH-m) is not detected after electrophoresis using HPPA as a substrate.

Amphibians↗
PubMed2006

Molecular cloning and characterization of a novel lactate dehydrogenase gene from Clonorchis sinensis.

From a Clonorchis sinensis adult worm cDNA library, we isolated a cDNA clone encoding a novel lactate dehydrogenase (LDH) gene which encoded a putative protein with a predicted molecular weight of 35.6 kDa. The optimum pH and temperature for the enzyme were 7.5 and 50 degrees C in the pyruvate reduction while 11 and 80 degrees C in the lactate oxidation reaction, respectively. CsLDH showed no substrate inhibition by high lactate and NAD(+) concentration, and the optimal pyruvate and optimal NADH concentrations were 10 and 0.5 mmol/l, respectively. The relative activities of these 2-oxocarboxylic acids were pyruvic acid>2-ketobutyrate>oxalacetic acid>alpha-ketoglutaric acid>phenylpyruvate. The cofactor 3-acetylpyridine adenine dinucleotide was much more effective than NAD(+). The cofactor analogs in which the nicotinamide ring is replaced by 3-pyridinealdehyde were lower activity cofactors, while the nicotinamide ring is replaced by nicotinic acid or thionicotinamide which is not a cofactor to CsLDH. The succinic acid and malic acid are not substrates of CsLDH. Cu(2+), Fe(2+), and Zn(2+) greatly inhibited the CsLDH activity both in the direction of pyruvate reduction and in the direction of lactate oxidation. The inhibition of CsLDH by gossypol may make gossypol a potential therapy drug or a lead compound for C. sinensis. Accordingly, the CsLDH may be a novel potential drug target.

Amino Acid Sequence↗
PubMed1982

Dopamine-derived tetrahydroisoquinolines. Novel inhibitors of dihydropteridine reductase.

Dopamine-derived tetrahydroisoquinolines, such as 3',4'-deoxynorlaudanosolinecarboxylic acid, higenamine-1-carboxylic acid, higenamine, and salsolinol, inhibit human liver dihydropteridine reductase noncompetitively with Ki values ranging from 1.5 to 90 microM. The enzyme is also inhibited noncompetitively by dopamine (Ki = 6 microM) and aminopterin (Ki = 100 microM) but uncompetitively by phenylpyruvic acid (Ki = 6.5 mM). These alkaloids may alter monoamine metabolism in mammals by inhibiting dihydropteridine reductase.

Alkaloids↗
PubMed1967

Lysosomal acid proteinase of rabbit liver.

1. Acid proteinase from rabbit liver lysosomes was purified about 1000-fold, on a protein basis. 2. The purification procedure involved isolation of a lysosomal-mitochondrial pellet and conversion of this into an acetone-dried powder. 3. The enzyme was extracted with an acidic buffer and subjected to column chromatography with DEAE-Sephadex and Sephadex G-100. 4. The molecular weight of the enzyme was 50000-52000. 5. Maximal activity against haemoglobin was obtained at pH3.2; serum albumin was attacked, but very much more slowly. 6. Several possible inhibitors of the enzyme were tested. Thiol-blocking reagents, several inhibitors of trypsin and chymotrypsin, and a chelating agent were without effect. 7. The enzyme was competitively inhibited by 3-phenylpyruvic acid at low concentrations. 8. Dithiothreitol caused rapid inactivation of the enzyme at pH8. 9. It is concluded that this enzyme is a form of cathepsin D, which may be widely distributed in lysosomes.

Animals↗
PubMed2003

Dendrimeric pyridoxamine enzyme mimics.

PAMAM dendrimers from generations 1-6 were synthesized with pyridoxamine in their core. They transaminated pyruvic and phenylpyruvic acids in water to alanine and phenylalanine, respectively, with Michaelis-Menten kinetics and high effectiveness compared with simple pyridoxamine. The largest dendrimers-similar in size to some globular proteins-were comparable in effectiveness to a previous polyethylenimine (PEI)-pyridoxamine catalyst, and to a protein-pyridoxamine catalyst, but not as effective as a previous PEI-pyridoxamine carrying lauryl hydrophobic groups. The new catalysts showed both general acid/base catalysis by their amino groups and hydrophobic binding of the phenylpyruvate substrate.

Biomimetic Materials↗
PubMed1994

Transport of 3-hydroxybutyrate by cultured rat brain astrocytes.

It is well established that 3-hydroxybutyrate can serve as an energy source for the brain. Since substrate utilization may be regulated in part by transport across the cellular membrane, we investigated the uptake of 3-hydroxybutyrate by primary cultures of rat brain astrocytes. Measurement of the net uptake indicated a saturable system and a Lineweaver-Burke type plot was consistent with a single carrier-mediated mechanism with a Km of 6.03 mM and a Vmax of 32.7 nmol/30 seconds/mg protein. The rate of uptake at pH 6.2 was more than ten times the rate at pH 8.2, with the rate at pH 7.4 being intermediate between these values, suggesting the possibility of cotransport with H+ or exchange with OH- (antiport). Mersalyl had only a slight effect on the transport of 3-hydroxybutyrate, suggesting that sulfhydryl groups are not involved in the transport of this monocarboxylic acid. Phenylpyruvate and alpha-ketoisocaproate also attenuated the transport, but lactate had only a marginal effect. These results suggest that the utilization of 3-hydroxybutyrate as an energy source by astrocytes is regulated in part by carrier-mediated transport and that the uptake system is different from the lactate transport system.

3-Hydroxybutyric Acid↗
PubMed1983

Eye findings in patients with phenylketonuria.

Untreated phenylketonuria (PKU) is characterized by excretion of phenylpyruvic acid in the urine and mental retardation. Reported eye abnormalities include photophobia (probably due to the albinoid iris), cataracts, and corneal opacities. Eleven patients in an institutionalized population of approximately 1,000 mentally retarded patients had PKU. Cataracts were found in six patients. One patient had bilateral phthisis bulbi and one patient had monocular phthisis. No corneal opacities were found otherwise. All patients with cataracts were middle-aged or had a history of severe self-induced trauma or treatment with high dosages of thioridazine hydrochloride. Albinism is associated with anomalous chiasmal routing of optic fibers and abnormal, extraocular motility. The ocular hypopigmentation of patients with PKU did not have the same results; all seeing patients were orthophoric. Although eye abnormalities are common in PKU except for hypopigmentation, none can be considered a direct effect of the inborn error of metabolism.

Adult↗
PubMed1990

Phenylalanine and its metabolites induce embryopathies in mouse embryos in culture.

The aim of this study was to determine the teratogenicity of phenylalanine (Phe) and Phe metabolites in neurulating mouse embryos. Therefore, the system of whole embryo culture was employed and D9 (neurulating) mouse embryos were exposed to Phe, phenylethylamine (PEA), phenylpyruvic acid (PPA), phenylacetic acid (PAA), 2-OH phenylacetic acid (2-OH PAA), and phenyl-lactic acid (PLA) at concentrations ranging from 0.01 mM to 10 mM for 24 hours. After 24 hours, embryos were examined for morphological abnormalities and protein content by the Lowry method. Phe at 1 and 6 mM concentrations was not teratogenic; however, 10 mM inhibited cranial neural tube closure in 82% of the embryos. PEA was the most toxic factor and concentrations of 1 and 10 mM were embryo-lethal, whereas neural tube closure defects (NTDs) were observed in 67% of the embryos at 0.1 mM. 2-OH PAA was the second most toxic metabolite with concentrations of 1 and 10 mM producing NTDs in 10 and 100% of the embryos, respectively. PLA and PAA produced no NTDs at concentrations of 1 mM, 60% at 5 mM, and 100% at 10 mM. Finally, PPA produced approximately 50% NTDs at both 1 mM and 10 mM concentrations. PLA, PAA, 2-OH PAA, and PPA produced a significant reduction in embryonic protein, and PEA and 2-OH PAA reduced yolk sac protein values. PEA, 2-OH PAA, PPA, PAA, and PLA also produced craniofacial abnormalities, i.e., incomplete expansion of the forebrain, collapse of the optic vesicle, and hypoplasia of the mandible and/or the maxilla.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗