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PubMed1997

Parasite sulphur amino acid metabolism.

This paper reviews current knowledge regarding the metabolism of the sulphur-containing amino acids methionine and cysteine in parasitic protozoa and helminths. Particular emphasis is placed on the unusual aspects of parasite biochemistry which may present targets for rational design of antiparasite drugs. In general, the basic pathways of sulphur amino acid metabolism in most parasites resemble those of their mammalian hosts, since the enzymes involved in (a) the methionine cycle and S-adenosylmethionine metabolism, (b) the trans-sulphuration sequence, (c) the transminative catabolism of methionine, (d) the oxidative catabolism of cysteine and (e) glutathione synthesis have been demonstrated variously in several helminth and protozoan species. Despite these common pathways, there also exist numerous differences between parasite and mammalian metabolism. Some of these differences are relatively subtle. For example, the biochemical properties (and primary amino acid structures) of certain parasite methionine cycle enzymes and S-adenosylmethionine decarboxylases differ from those of the corresponding mammalian enzymes, and nematodes and trichomonads possess a novel, non-mammalian form of the trans-sulphuration enzyme cystathionine beta-synthase. The most profound differences between parasite and mammalian biochemistry relate to a number of unusual enzymes and thiol metabolites found in parasitic protozoa. In certain protozoa the pathway for methionine recycling from 5'-methylthioadenosine differs markedly from the mammalian route, and involves 2 exclusively microbial enzymes. Trypanosomatid protozoa contain the non-mammalian antioxidant thiol compounds ovothiol A and trypanothione, together with unique trypanothione-linked enzymes. Specific anaerobic protozoa possess another exclusively microbial enzyme, methionine gamma-lyase, which catabolises methionine (and homocysteine); the physiological significance of these non-mammalian activities is not fully understood. These unusual features offer opportunities for chemotherapeutic exploitation, and in some cases represent metabolic similarities with bacteria. Additionally, some anaerobic protozoa contain unidentified thiols and this implies the presence of further unusual enzymes/pathways in these organisms. So far, no truly unique targets for chemotherapy have been found in helminth sulphur amino acid metabolism, and to some degree this reflects the relative lack of detailed study in the area.

Amino Acids, Sulfur↗
PubMed2001

Ketogenic diet, amino acid metabolism, and seizure control.

The ketogenic diet has been utilized for many years as an adjunctive therapy in the management of epilepsy, especially in those children for whom antiepileptic drugs have not permitted complete relief. The biochemical basis of the dietary effect is unclear. One possibility is that the diet leads to alterations in the metabolism of brain amino acids, most importantly glutamic acid, the major excitatory neurotransmitter. In this review, we explore the theme. We present evidence that ketosis can lead to the following: 1) a diminution in the rate of glutamate transamination to aspartate that occurs because of reduced availability of oxaloacetate, the ketoacid precursor to aspartate; 2) enhanced conversion of glutamate to GABA; and 3) increased uptake of neutral amino acids into the brain. Transport of these compounds involves an uptake system that exchanges the neutral amino acid for glutamine. The result is increased release from the brain of glutamate, particularly glutamate that had been resident in the synaptic space, in the form of glutamine. These putative adaptations of amino acid metabolism occur as the system evolves from a glucose-based fuel economy to one that utilizes ketone bodies as metabolic substrates. We consider mechanisms by which such changes might lead to the antiepileptic effect.

Amino Acids↗
PubMed2004

Regulation of branched-chain amino acid metabolism and pharmacological effects of branched-chain amino acids.

Significant evidence of the pharmacological and physiological effects of branched-chain amino acids (BCAA) has accumulated, attracting the interest of not only clinicians but also basic medical researchers. We summarize here the characteristic features of BCAA catabolism, focusing on the initial two enzymes in the pathway, branched-chain aminotransferase and branched-chain alpha-keto acid dehydrogenase complex. In addition, we describe a unique characteristic of the valine catabolic pathway. Finally, we present evidence obtained in animal studies that indicates that BCAA treatment may be appropriate for liver cirrhosis, but not acute liver failure.

Journal Article↗
PubMed1977

Role of transport systems in amino acid metabolism: leucine toxicity and the branched-chain amino acid transport systems.

The livR locus, which leads to a trans-recessive derepression of branched-chain amino acid transport and periplasmic branched-chain amino acid-binding proteins, is responsible for greatly increased sensitivity toward growth inhibition by leucine, valine, and serine and, as shown previously, for increased sensitivity toward toxicity by branched-chain amino acid analogues, such as 4-azaleucine or 5',5',5'-trifluoroleucine. These phenotypes are similar to those of relA mutants; however, the livR mutants retain the stringent response of ribonucleic acid synthesis. However, an increase in the rate of transport or in the steady-state intracellular level of amino acids in the livR strain cannot completely account for this sensitivity. The ability of the LIV-I transport system to carry out exchange of pool amino acids for extracellular leucine is a major factor in leucine sensitivity. The previous finding that inhibition of threonine deaminase by leucine contributes to growth inhibition is confirmed by simulating the in vivo conditions using a toluene-treated cell preparation with added amino acids at levels corresponding to the internal pool. The relationship between transport systems and corresponding biosynthetic pathways is discussed and the general principle of a coordination in the regulation of transport and biosynthetic pathways is forwarded. The finding that the LIV-I transport system functions well for amino acid exchange in contrast to the LIV-II system provides another feature that distinguishes these systems in addition to previously described differences in regulation and energetics.

Biological Transport, Active↗
PubMed1980

Amino acid metabolism and the liver in renal failure.

The study of amino acid metabolism across the splanchnic organs can be useful for investigating derangements in nitrogen metabolism in chronic renal insufficiency. For this purpose, arterial-hepatic venous differences for 19 free amino acids, ammonia and urea, determined in whole blood, were measured in six patients with chronic renal insufficiency and in six subjects with normal renal function. In normal conditions, the hepatosplanchnic bed significantly extracts glutamine, alanine, glycine, serine, threonine, lysine, arginine, phenylalanine, valine, tyrosine, histidine, leucine, and ammonia, and releases glutamate, citrulline, and urea. In chronic renal insufficiency, glutamine uptake decreases, serine, valine and ammonia uptake disappears, proline extraction becomes present, citrulline output is no longer detectable and glutamate release falls slightly. Furthermore, the splanchnic uptake of ammonia and the output of urea into the hepatic veins are markedly reduced. Since glutamine and ammonia are major substrates for urea synthesis, their lower uptakes, as observed in renal insufficiency, may be consistent with the reduced urea output. The changes in splanchnic metabolism observed in chronic renal insufficiency have a minor effect on the abnormalities in circulating amino acids. Finally, the splanchnic metabolism shows an important role in the homeostasis of circulating tyrosine and proline.

Adult↗
PubMed1990

Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis.

Recently, the excitatory amino acid neurotransmitter glutamate was implicated in the pathogenesis of a variety of chronic degenerative neurological diseases in humans and animals. This report describes abnormalities in excitatory amino acids in the central nervous system of 18 patients with amyotrophic lateral sclerosis (ALS). The concentration of the excitatory amino acids glutamate and aspartate in the cerebrospinal fluid were increased significantly (p less than 0.01) by 100 to 200% in patients with ALS. Similarly, the concentrations of the excitatory neuropeptide N-acetyl-aspartyl glutamate and its metabolite, N-acetyl-aspartate, were elevated twofold to threefold in the cerebrospinal fluid from the patients. There was no relationship between amino acid concentrations and duration of disease, clinical impairment, or patient age. In the ventral horns of the cervical region of the spinal cord, the level of N-acetyl-aspartyl glutamate and N-acetyl-aspartate was decreased by 60% (p less than 0.05) and 40% (p less than 0.05), respectively, in 8 patients with ALS. Choline acetyltransferase activity was also diminished by 35% in the ventral horn consistent with motor neuron loss. We conclude that excitatory amino acid metabolism is altered in patients with ALS. Based on neurodegenerative disease models, these changes may play a role in motor neuron loss in ALS.

Adult↗
PubMed1997

Effect of endurance training on ammonia and amino acid metabolism in humans.

Few studies examine ammonia and amino acid metabolism in response to endurance training. Trained humans generally experience less increase in plasma ammonia during either prolonged or intense exercise. This is probably a reflection of reduced ammonia production and release from the active muscle; it could be a reflection of decreased AMP deaminase activity, decreased glutamate dehydrogenase activity, and/or increased alanine and glutamine formation. Little is known regarding the associated enzyme systems in humans, but in experiments with animal models, aerobic training decreases AMP deaminase and increases the enzymes of amino acid transamination and oxidation.

AMP Deaminase↗
PubMed2003

Evolution of amino acid metabolism inferred through cladistic analysis.

Because free amino acids were most probably available in primitive abiotic environments, their metabolism is likely to have provided some of the very first metabolic pathways of life. What were the first enzymatic reactions to emerge? A cladistic analysis of metabolic pathways of the 16 aliphatic amino acids and 2 portions of the Krebs cycle was performed using four criteria of homology. The analysis is not based on sequence comparisons but, rather, on coding similarities in enzyme properties. The properties used are shared specific enzymatic activity, shared enzymatic function without substrate specificity, shared coenzymes, and shared functional family. The tree shows that the earliest pathways to emerge are not portions of the Krebs cycle but metabolisms of aspartate, asparagine, glutamate, and glutamine. The views of Horowitz (Horowitz, N. H. (1945) Proc. Natl. Acad. Sci. U. S. A. 31, 153-157) and Cordón (Cordón, F. (1990) Tratado Evolucionista de Biologia, Aguilar, Madrid, Spain), according to which the upstream reactions in the catabolic pathways and the downstream reactions in the anabolic pathways are the earliest in evolution, are globally corroborated; however, with some exceptions. These are due to later opportunistic connections of pathways (actually already suggested by these authors). Earliest enzymatic functions are mostly catabolic; they were deaminations, transaminations, and decarboxylations. From the consensus tree we extracted four time spans for amino acid metabolism development. For some amino acids catabolism and biosynthesis occurred at the same time (Asp, Glu, Lys, Leu, Ala, Val, Ile, Pro, Arg). For others ultimate reactions that use amino acids as a substrate or as a product are distinct in time, with catabolism preceding anabolism for Asn, Gln, and Cys and anabolism preceding catabolism for Ser, Met, and Thr. Cladistic analysis of the structure of biochemical pathways makes hypotheses in biochemical evolution explicit and parsimonious.

Amino Acids↗
PubMed1993

Protein and amino acid metabolism in cancer cachexia: investigative techniques and therapeutic interventions.

Cancer cachexia is a complex syndrome characterized primarily by diminished nutrient intake and progressive tissue depletion that is manifest clinically as anorexia and host weight loss. The gradual loss of host protein stores is central to this process. This review outlines the techniques that have been used to evaluate human amino acid metabolism, their application in patients with cancer cachexia, and possible therapeutic interventions designed to overcome alterations in host protein and amino acid metabolism associated with malignant cachexia. The techniques of nitrogen balance and 3-methylhistidine excretion provide indirect estimates of overall nitrogen metabolism and skeletal muscle myofibrillar protein breakdown. Measurement of circulating amino acid concentrations, particularly when combined with assessment of arterial-venous differences and regional amino acid balance allows for investigation of interorgan amino acid metabolism. One of the most significant advances in in vivo amino acid metabolic research has been the development of labeled amino acid tracer studies to evaluate whole body and regional amino acid kinetics. The use of stable and unstable amino acid isotopes in these techniques is reviewed in detail. Virtually all of these techniques have now been employed in the evaluation of human cancer cachexia. The results of studies evaluating amino acid concentrations, regional amino acid balance, and 3-methylhistidine excretion are summarized. The use of regional and whole body kinetic studies in cancer cachexia are reviewed extensively. Most investigators have observed increased rates of whole body protein turnover, synthesis, and catabolism in both weight-stable and weight-losing cancer patients. Some studies have suggested a relationship between the extent of disease and the degree of aberration in amino acid kinetic parameters. Investigators have attempted to reverse some of these alterations by provision of substrate (nutritional support) or administration of specific pharmacologic or anabolic agents such as hydrazine sulfate, insulin, growth hormone, and beta-2 agonists. The role of total parenteral nutrition (TPN) in cancer and its effects on protein and amino acid kinetics and tumor growth are addressed. The possible benefits of specific amino acid nutritional formulations with increased branched chain amino acids, arginine, and glutamine are reviewed. Although many of these approaches appear promising, significant impact on clinically definable parameters remains to be demonstrated. A better understanding of the underlying protein catabolic mechanisms of cancer cachexia will likely lead to more effective therapies to reverse the protein calorie malnutrition associated with cancer cachexia.

Amino Acids↗
PubMed1986

Sulfur amino acid metabolism in chronic relapsing pancreatitis.

Sulfur amino acid (SAA) metabolism was studied in patients with chronic relapsing pancreatitis (CRP) before and during treatment and compared with results from patients with uncomplicated cholelithiasis, before and after surgery, receiving an identical nutritional support. CRP resulted in decreased total sulfur and inorganic sulfate excretions. Although the nutritional therapy per se accentuated these results, a reduced ability to convert SAAs to inorganic sulfate was seen during the whole investigation. Initially, CRP patients showed a raised serum concentration of inorganic sulfate, implicating an altered renal handling of the compound. Increased outputs of SAAs, N-acetylcysteine and mercaptolactate were seen in CRP patients parallel to a raised leukocyte methionine level, probably a consequence of the catabolic state and a limited utilization of SAAs. During therapy a normalization was achieved. Reduced total and free glutathione concentrations in leukocytes were found in CRP, and it was more pronounced for the free form. This result could be due to a reduced synthesis and increased intracellular oxidation of glutathione as a result of the decrease in ethanol.

Adult↗
PubMed1992

Diverse effects of insulin-like growth factor I on glucose, lipid, and amino acid metabolism.

The metabolic effects of recombinant human insulin-like growth factor I (rhIGF-I) on glucose, amino acid, and free fatty acid (FFA) metabolism were examined in nine healthy nonobese subjects. Each received a 3-h primed continuous infusion of rhIGF-I (20 micrograms/kg bolus, 0.4 microgram.kg-1.min-1) while maintaining euglycemia using an exogenous glucose infusion. Total IGF-I levels increased from 125 +/- 11 to 444 +/- 22 ng/ml, and free IGF-I levels rose from undetectable to 73 +/- 5 ng/ml. Insulin levels fell from 95 +/- 9 to 64 +/- 8 pM, and C-peptide fell from 453 +/- 48 to 206 +/- 29 pM; circulating glucagon levels also declined from 72 +/- 9 to 42 +/- 4 pg/ml, rhIGF-I produced a two- to threefold increase in glucose uptake as measured by [3H] glucose (from 10.3 +/- 0.6 to 27.4 +/- 3 mumol.kg-1.m-1), and, despite the fall in insulin secretion, there was a marked 60-70% inhibition of hepatic glucose production. Furthermore, FFA and branched-chain amino acids declined by 40-60% (411 +/- 58 to 165 +/- 36 and 406 +/- 23 to 219 +/- 14 microM, respectively). Our data demonstrate that rhIGF-I has potent effects on glucose (hepatic and peripheral), lipid, and amino acid metabolism in normal humans. The scope of the actions of rhIGF-I closely resemble those of insulin, despite a concomitant inhibitory effect on insulin secretion.

Adult↗
PubMed1997

Effects of ketone bodies on astrocyte amino acid metabolism.

The effects of acetoacetate and 3-hydroxybutyrate on glial amino acid metabolism were studied in primary cultures of astrocytes. The exchange of nitrogen among amino acids was measured with 15N as a metabolic probe and gas chromatography-mass spectrometry as a tool with which to quantify isotope abundance. Addition of either acetoacetate or 3-hydroxybutyrate (5 mM) to the incubation medium did not alter the initial rate of appearance of [15N]glutamate in the glia, but it did inhibit transamination of glutamate to [15N]aspartate. Addition of acetoacetate also inhibited formation of [2-(15)N]glutamine, but 3-hydroxybutyrate had a stimulatory effect. The presence in the medium of sodium acetate (5 mM) was also associated with diminished production of [15N]aspartate and [2-(15)N]glutamine with [15N]glutamate as precursor. Studies with [2-(15)N]glutamine as precursor indicated that treatment of the astrocytes with ketone bodies did not alter flux through the glutaminase pathway. Nor did the presence of the ketone bodies reduce significantly the flux of nitrogen from [15N]GABA to [2-(15)N]glutamine when the former species served as a metabolic tracer. The concentration of internal citrate increased in the presence of acetoacetate, 3-hydroxybutyrate, and acetate. Studies with purified sheep brain glutamine synthetase showed that citrate inhibited this enzyme. These findings are considered in terms of the known anticonvulsant effect of a ketogenic diet.

3-Hydroxybutyric Acid↗
PubMed2001

Whole-body nitrogen and splanchnic amino acid metabolism differ in rats fed mixed diets containing casein or its corresponding amino acid mixture.

Whole-body and splanchnic metabolism of dietary amino acids derived from casein (CAS) or the corresponding crystalline L-amino acid mixture (AA) were compared. Male adult rats were adapted for 9 d to two isoenergetic, isonitrogenous diets (15 g/100 g protein, 5 g/100 g fat) containing either CAS or AA. On d 10, the rats were fed a single mixed meal (3 g dry mass) containing either intrinsically (13)C-labeled goat casein or the amino acid mixture containing [U-(13)C(6)] leucine and [alpha-(15)N] lysine. Rats were killed before and 1, 3, 5 and 7 h after meal ingestion and samples of plasma, stomach wall and contents, small intestine and liver were collected. (13)C and (15)N enrichments of free and protein-bound amino acids in plasma and tissues were analyzed by gas chromatography-combustion isotope ratio mass spectrometry. Urinary nitrogen excretion was higher (P < 0.05) and weight gain lower (P < 0.05) in rats given the AA diet, indicating a lower whole-body net protein synthesis. Free (13)C-leucine from the AA diet appeared in the intestinal mucosa free pool more rapidly (P < 0.05) than the CAS-(13)C-leucine, probably due to the faster transit through the stomach of the AA group. However, the incorporation of dietary leucine into plasma and liver proteins was higher in the CAS group 7 h after the meal (P < 0.05), whereas lysine incorporation into liver protein was higher in the AA group (P < 0.05). We conclude that whole-body protein homeostasis is better supported by dietary casein-bound than crystalline free amino acids, and that protein-bound leucine, but not lysine, is used more efficiently for liver protein synthesis than dietary free leucine.

Amino Acids↗
PubMed1986

[Clinical study of protein and amino acids metabolism in surgical infection--significance of administration of branched chain amino acids].

Anastomotic leakage and fistula of alimentary tract are accompanied by peritonitis because of exudation of contents in the digestive canal. In order to inquire about metabolism of protein and amino acids in surgical infection, this study was performed by the method of a time related cross-over trial, comparing high branched chain amino acids (BCAA) solution with low BCAA solution. The following results were obtained. When metabolism is physiologically compensated in infection, it was suggested that there appeared to be gluconeogenesis, ureagenesis and a liver disturbance accompanied in the early phase of sepsis. Administration of BCAA leads to an inhibition of muscle protein break down and a promotion of visceral protein synthesis in the case of severe infection. Administration of BCAA enriched amino acids solution have an important therapeutic measure under severe stressed condition and a significant role in medicine.

Adult↗
PubMed1994

Inborn errors of amino acid metabolism in north India.

We screened 2560 referred cases for inborn errors of amino acid metabolism by chemical tests and thin-layer chromatography of urine/plasma. In 62(2.4%) cases, eleven inherited Mendelian disorders of amino acids were identified. The four commonest disorders were homocystinuria, alcaptonuria, maple syrup urine disease and nonketotic hyperglycinaemia. Ornithinaemia was detected in two cases (0.08%), and phenylketonuria and cystinuria in two cases each (0.08%). Generalized hyperaminoacidurias were found in 90 (3.52%) subjects. The frequency pattern of the various amino acid disorders in North India was found to be remarkably different from that observed in the West.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

[Amino acid metabolism in neurodegenerative diseases].

Although various neurological diseases occur in patients with inborn error of metabolism of amino acids, amino acids also act as neurotransmitters. Glutamic acid, aspartic acid and glycine play roles as an excitatory neurotransmitter, but exert a neurodegenerative effect in case of the excessive release. Extensive studies have recently been performed on glutamate receptors, especially N-methyl-D-aspartate (NMDA) receptor in the hippocampus. Alzheimer brain shows a decreased number of NMDA receptors in the frontal cortex. The parkinsonian changes caused by MPTP is abolished by the administration of a NMDA antagonist. gamma-Aminobutyric acid (GABA) acts as an inhibitory amino acid. The content of GABA is low in the striatum of patients with Huntington's disease. The number of NMDA receptor is decreased also in Huntington striatum. These observations may give a clue for the prevention of various neurodegenerative diseases.

Alzheimer Disease↗