The metabolism of amino acids

An adult has a requirement for a dietary intake of protein because there is continual oxidation of amino acids as a source of metabolic fuel and for gluconeogenesis in the fasting state. In the fed state, amino acids in excess of immediate requirements for protein synthesis are oxidized. Overall, for an adult in nitrogen balance, the total amount of amino acids being metabolized will be equal to the total intake of amino acids in dietary proteins. 

Amino acids are also required for the synthesis of a variety of metabolic products, 

In general, the amounts of amino acids required for synthesis of these products are small compared with the requirement for maintenance of nitrogen balance and protein turnover. 

The initial step in the metabolism of amino acids is the removal of the amino group (-NH ), leaving the carbon skeleton of the amino acid. Chemically, these carbon skeletons are ketoacids (more correctly, they are oxo-acids). A ketoacid has a —C=0 group in place of the HC-NH group of an amino acid the metabolism of ketoacids is discussed in section 9.3.2. 

There is an active D-amino acid oxidase in the kidneys, which acts to deaminate, and hence detoxify, the small amounts of D-amino acids that arise from bacterial proteins. The ketoacids resulting from the action of D-amino acid oxidase on D-amino acids can undergo transamination (section 9.3.1.2) to yield the L-isomers. This means that, at least to a limited extent, D-amino acids can be isomerized and used for protein synthesis. Although there is evidence from experimental animals that D-isomers of (some of) the essential amino acids can be used to maintain nitrogen balance, there is little information on utilization of D-amino acids in human beings. 

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The metabolism of amino acids is complex and is described in standard text books. These are usually converted by aminotransferases to the corresponding 2-oxoacids which are partly oxidized in the matrix of muscle mitochondria and partly exported to the liver. Glutamate and aspartate yield 2-oxoglutarate and oxaloacetate, respectively, which enter the citrate cycle directly, and other 2-... 

A completely distinct enzyme has been found in a number of organisms, which carry out the metabolism of amino acids. In this group, a pyruvoyl group is covalently bound to the active enzyme that is produced from a proenzyme in a self-maturation process (Toms et al. 2004). The proenzyme contains a serine residue that undergoes rearrangement to an ester followed by conversion into the (3-chain of the enzyme and a dehydroalanine residne that forms the A-terminal pyruvoyl group of the a-chain. This type of enzyme has been fonnd for a number of important decarboxylations ... 

The alanine cycle accomplishes the same thing as the Cori cycle, except with an add-on feature (Fig. 17-11). Under conditions under which muscle is degrading protein (fasting, starvation, exhaustion), muscle must get rid of excess carbon waste (lactate and pyruvate) but also nitrogen waste from the metabolism of amino acids. Muscle (and other tissues) removes amino groups from amino acids by transamination with a 2-keto acid such as pyruvate (oxaloacetate is the other common 2-keto acid). 

The calorific capacity of amino acids is comparable to that of carbohydrates so despite their prime importance in maintaining structural integrity of cells as proteins, amino acids may be used as fuels especially during times when carbohydrate metabolism is compromised, for example, starvation or prolonged vigorous exercise. Muscle and liver are particularly important in the metabolism of amino acids as both have transaminase enzymes (see Figures 6.2 and 6.3 and Section 6.4.2) which convert the carbon skeletons of several different amino acids into intermediates of glycolysis (e.g. pyruvate) or the TCA cycle (e.g. oxaloacetate). Not all amino acids are catabolized to the same extent... 

Pyridoxal phosphate is a required coenzyme for many enzyme-catalyzed reactions. Most of these reactions are associated with the metabolism of amino acids, including the decarboxylation reactions involved in the synthesis of the neurotransmitters dopamine and serotonin. In addition, pyridoxal phosphate is required for a key step in the synthesis of porphyrins, including the heme group that is an essential player in the transport of molecular oxygen by hemoglobin. Finally, pyridoxal phosphate-dependent reactions link amino acid metabolism to the citric acid cycle (chapter 16). 

Ammonia is generated mainly from the metabolism of amino acids and from the catabolism of purine and pyrimidine bases, which are produced from nucleic acids. Since it is toxic, it must be converted to a non-toxic compound for excretion from the body. This is achieved via the ornithine cycle, more usually known as the urea cycle. 

Among the numerous enzymes that utilize pyridoxal phosphate (PLP) as cofactor, the amino acid racemases, amino acid decarboxylases (e.g., aromatic amino acids, ornithine, glutamic acid), aminotransferases (y-aminobutyrate transaminase), and a-oxamine synthases, have been the main targets in the search for fluorinated mechanism-based inhibitors. Pharmaceutical companies have played a very active role in this promising research (control of the metabolism of amino acids and neuroamines is very important at the physiological level). 

Disturbances in the metabolism of amino acids occur mainly with the aromatic amino acids, such as phenylalanine and tyrosine. The error may be caused by the deficiency of a specific enzyme, a defect in the enzyme itself, or by the absence of factors necessary for the proper function of the enzyme. 

Why have many inborn errors been found in the metabolism of amino acids in humans but none in glycolysis, the citric acid cycle, or electron transport ... 

Part 6, Metabolism of Nitrogen-Containing Compounds, is concerned mostly with the metabolism of amino acids and nucleotides. Chapter 24, the last chapter in this part, deals with the integration of metabolism. 

Vitamin Be [pyridoxine) Men 1.3-1.7 mg/d Women 1.3-1.5 mg/d Coenzyme in the metabolism of amino acids and glycogen No adverse effects have been reported ... 

Vitamin Be has a central role in the metabolism of amino acids in transaminase reactions (and hence the interconversion and catabolism of amino acids and the synthesis of nonessential amino acids), in decarboxylation to yield biologically active amines, and in a variety of elimination and replacement reactions. It is also the cofactor for glycogen phosphorylase and a variety of other enzymes. In addition, pyridoxal phosphate, the metabolically active vitamer, has a role in the modulation of steroid hormone action and the regulation of gene expression. 

Higher alcohols Higher alcohols are produced as a deviation of the metabolism of amino acids. Higher alcohols are produced when keto acids corresponding to the carbon skeleton from the different amino acids are decarboxylated and reduced. Higher alcohols are normally below their limit of detection but they are the precursors of some esters, which have a large sensory impact. 

The metabolism of amino acids does not affect the taste, but is problematic at a toxicological level, because it increases the concentrations of biogenic amines and ethyl carbamate precursors in wine. 

Tetrahydrofolate, a carrier of activated one-carbon units, plays an important role in the metabolism of amino acids and nucleotides. This coenzyme carries one-carbon units at three oxidation states, which are interconvertible most reduced—methyl intermediate—methylene and most oxidized—formyl, formimino, and methenyl. The major donor of activated methyl groups is -adenosylmethionine, which is synthesized by the transfer of an adenosyl group from ATP to the sulfur atom of methionine. -Adenosylhomocysteine is formed when the activated methyl group is transferred to an acceptor. It is hydrolyzed to adenosine and homocysteine, the latter of which is then methylated to methionine to complete the activated methyl cycle. 

The liver plays an essential part in the metabolism of amino acids, (s. p. 38) (s. tab. 3.6) For this reason, a shift of the amino acid profile in the plasma has to be reckoned with in severe liver diseases. There is clear evidence of an increase in aromatic amino acids as well as a reduction in branched-chain amino acids, (s. tab. 15.1) Extrahepatic mechanisms (glucagon, insulin, lactate acidosis, etc.) can also effect significant changes to the amino acid spectrum. Multiple biochemical repercussions may result from this, affecting the development of HE. (8, 13, 45, 48, 53, 61, 68, 71)... 

Greenstein, J.R, Winitz, M., GnUino, P, Birnbanm, S.M., Otey, MC. Studies on the metabolism of amino acids and related compounds in vivo. III. Prevention of ammonia toxicity by arginine and related compounds. Arch. Biochem. 1956 64 342—354... 

PLP is the cofactor for a large number of enzymes used in the metabolism of amino acids and related compounds. Some of these enzymes are listed in Table 9.3. In the aminotransferases, the cofaefor form shifts between PLP and PME In glutamate-oxaloacetate aminotransferase, for example, glutamate reacts with the enzyme bound cofactor and is converted to ot-ketoglutarate. Its amino group remains bound to the cofactor, which is changed to the pyridoxamine phosphate form ... 

Three major factors are considered as important in determining the supply of tryptophan to the brain leading to serotonin synthesis (1) the extent of binding of tryptophan to serum albumin, which influences the pool of free (unbound) tryptophan that interacts with the amino acid carrier mechanism located at the blood-brain barrier, (2) the plasma tryptophan concentrations, and (3) the plasma concentration of other large neutral amino acids (LNAA), which compete with tryptophan for uptake into brain. Each factor can be influenced by the nutritional or hormonal status of the host and also by interorgan relationships in the metabolism of amino acids. 

Ammonia lyases in their natural role are involved in the metabolism of amino acids and also play a role in, for instance, the degradation of amino sugars, but only a limited amount of these enzymes have been characterized biochemically. Application of a broad range of different ammonia and lyases in organic chemical synthesis on an industrial scale has thus far not occurred, which is due to both their limited commercial availability and their lack of stability under process conditions. Exceptions are the commercially applied aspartase, which is an ammonia lyase that is utilized for the synthesis of L-aspartic acid from fumaric acid, and phenylalanine lyase. The latter is an example of a commercial application of an ammonia lyase in a process for the production of L-phenylalanine and more importantly L-phenylalanine derivatives. 

For documentation purposes, a much-abbreviated reaction scenario for glutaminolysis is shown in Figure 3.3. Glutamine is an amino acid, and glutaminolysis is only part of the more general topic of the metabolism of amino acids, which is covered in the standard texts and references on biochemistry. 

Pyridoxal phosphate and its close relative, pyridoxamine phosphate (Fig. 1, 6) participate in a multiplicity of different biological processes, most noteworthy amongst these being the reaction involved in the metabolism of amino acids [3-6]. Several dozen enzymes are known whose activities are dependent on the presence of pyridoxal phosphate in their active sites. Our current view regarding the niechanisms of pyridoxal-P-dependent transformations is based on the inspired suggestion originally made in 1953, independently by Braunstein and Shemyakin [7] in the Soviet Union, and Snell and his coworkers [8] in the United States. Before considering the basic tenets of the Braunstein-Snell hypothesis we examine the nature of the chemical problems involved in the metabolism of amino acids. In the later sections we shall note that the key event in the metabolism of amino acids is either the... 

Vitamin B6 has been shown to be essential in many biochemical reactions that occur in plants and animals. Although it may occur in any one of the three forms listed above, the compound usually acts as the phosphate ester, pyridoxine phosphate. Pyridoxine phosphate functions as a coenzyme in the transformation of amino acids, the building blocks from which proteins are made. A coenzyme is a chemical compound that works with an enzyme to catalyze some essential chemical reaction in the body. Pyridoxine phosphate appears to be necessary for the synthesis of proteins from amino acids as well as the metabolism of amino acids to produce energy needed for normal body functioning. 

In comparison with carbohydrate and lipid metabolism, the metabolism of amino acids is complex. We must be concerned not only with the fate of the carbon atoms of the amino acids but also with the fate of the nitrogen During their metabolism, amino acids travel in the blood from one tissue to another. Ultimately, most of the nitrogen is converted to urea in the liver and the carbons are oxidized to CO2 and H2O by a number of tissues (Fig. 38.1). 

C. Role of Glutamate in the Metabolism of Amino Acid Nitrogen... 

Glutamate plays a pivotal role in the metabolism of amino acids. It is involved in both synthesis and degradation. 

CHAPTER 42 / INTERTISSUE RELATIONSHIPS IN THE METABOLISM OF AMINO ACIDS... 

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