Lysine transamination

Lysine. Unpublished results based on changes in urinary lysine and amino N output (113) indicate that more than 80% of orally administered unnatural lysine is utilized by man. This seems remarkable in view of the observations in the rat of Weissman and Schoenheimer (126) that lysine transaminates slowly if at all and that deamination of lysine is biologically irreversible. Attention is called to the failure of administration of d (—)-lysine to induce the nausea or dizziness observed in the subjects maintained on a lysine-deficient diet. The availability of d-lysine (127) and its derivatives (128) has been studied in the rat by Neuberger. 

The mechanism of the first part of transamination is shown in Figure 29.14. The process begins with reaction between the a-amino acid and pyridoxal phosphate, which is covalently bonded to the aminotransferase by an iminc linkage between the side-chain -NTI2 group of a lysine residue and the PLP aldehyde group. Deprotonation/reprotonation of the PLP-amino acid imine in steps 2 and 3 effects tautomerization of the imine C=N bond, and hydrolysis of the tautomerized imine in step 4 gives an -keto acid plus pyridoxamine... 

Step 1 of Figure 29.14 Transimination The first step in transamination is trans-imination—the reaction of the PLP—enzyme imine with an a-amino acid to give a PLP—amino acid imine plus expelled enzyme as the leaving group. The reaction occurs by nucleophilic addition of the amino acid -NH2 group to the C=N bond of the PLP imine, much as an amine adds to the C=0 bond of a ketone or aldehyde in a nucleophilic addition reaction (Section 19.8). The pro-tonated diamine intermediate undergoes a proton transfer and expels the lysine amino group in the enzyme to complete the step. 

Write all the steps in the transamination reaction of PMP with a-ketoglutarate plus a lysine residue in the enzyme to give the PLP-enzyme inline plus glutamate. 

Transamination is not restricted to a-amino groups. The 5-amino group of ornithine—but not the e-amino group of lysine—readily undergoes transamination. Serum levels of aminotransferases are elevated in some disease states (see Figure 7-11). 

Removal of a-amino nitrogen by transamination (see Figure 28-3) is the first catabolic reaction of amino acids except in the case of proline, hydroxyproline, threonine, and lysine. The residual hydrocarbon skeleton is then degraded to amphibolic intermediates as outhned in Figure 30-1. 

Neither nitrogen of lysine undergoes transamination. Metabolic diseases of lysine catabolism include periodic and persistent forms of hyperlysinemia-ammonemia. 

After formation of the aldimine, numerous factors in the enzyme facilitate deprotonation of the a-carbon (Fig. 3, Step II). The lysine liberated by transimi-nation is utilized as a general base and is properly oriented for effective deprotonation [11]. Furthermore, the inductive effects of the ring system are tuned to increase the stabilization of the quinoid intermediate. For example, the aspartate group that interacts with the pyridyl nitrogen of the co enzyme promotes proto-nation to allow the ring to act as a more effective electron sink. In contrast, in alanine racemase, a less basic arginine residue in place of the aspartic acid is believed to favor racemization over transamination [12]. 

Pyridoxal phosphate (4) is the most important coenzyme in amino acid metabolism. Its role in transamination reactions is discussed in detail on p. 178. Pyridoxal phosphate is also involved in other reactions involving amino acids, such as decarboxylations and dehydrations. The aldehyde form of pyridoxal phosphate shown here (left) is not generally found in free form. In the absence of substrates, the aldehyde group is covalently bound to the e-amino group of a lysine residue as aldimine ( Schiffs base ). Pyridoxamine phosphate (right) is an intermediate of transamination reactions. It reverts to the aldehyde form by reacting with 2-oxoacids (see p. 178). 

The precursors of true alkaloids and protoalkaloids are aminoacids (both their precursors and postcursors), while transamination reactions precede pseudoalkaloids (Tables 1 and 10). It is not difficult to see that from all aminoacids only a small part is known as alkaloid precursors (Table 19). Both true and proto alkaloids are synthesized mainly from the aromatic amino acids, phenylalanine, tyrosine (isoquinoline alkaloids) and tryptophan (indole alkaloids). Lysine is the... 

Tranexamic acid (Cyklokapron, Transamin) is a synthetic derivative of the amino acid lysine. It exerts its antifibrinolytic effect through the reversible blockade of lysine binding sites on plasminogen molecules. 

Lysine, an exclusively ketogenic amino acid, is unusual in that nei ther of its amino groups undergoes transamination as the first step in catabolism. Lysine is ultimately converted to acetoacetyl CoA. 

This is followed by ATP-dependent reduction to the aldehyde.2643 The final step of transamination is not accomplished in the usual way (with a PLP-dependent enzyme), but through formation of a Schiff base with glutamate and reduction to saccharopine.265 Oxidation now produces the Schiff base of lysine with 2-oxoglutarate. 

Another variation is used by Pseudomonas (34 (Eq. 24-31). Beta-lysine is acetylated on N-6, then undergoes transamination to a 2-oxo acid and removal of the first two carbons as acetyl-CoA. The resulting 4-aminobutyrate is then converted to succinate via succinate semialdehyde.295... 

The alanine racemization catalyzed by alanine racemase is considered to be initiated by the transaldimination (Fig. 8.5).26) In this step, PLP bound to the active-site lysine residue forms the external Schiff base with a substrate alanine (Fig. 8.5, 1). The following a-proton abstraction produces the resonance-stabilized carbanion intermediates (Fig. 8.5, 2). If the reprotonation occurs on the opposite face of the substrate-PLP complex on which the proton-abstraction proceeds, the antipodal aldimine is formed (Fig. 8.5,3). The subsequent hydrolysis of the aldimine complex gives the isomerized alanine and PLP-form racemase. The random return of hydrogen to the carbanion intermediate is the distinguishing feature that differentiates racemization from reactions catalyzed by other pyridoxal enzymes such as transaminases. Transaminases catalyze the transfer of amino group between amino acid and keto acid, and the reaction is initiated by the transaldimination, followed by the a-proton abstraction from the substrate-PLP aldimine to form a resonance-stabilized carbanion. This step is common to racemases and transaminases. However, in the transamination the abstracted proton is then tranferred to C4 carbon of PLP in a highly stereospecific manner The re-protonation occurs on the same face of the PLP-substrate aldimine on which the a-proton is abstracted. With only a few exceptions,27,28) each step of pyridoxal enzymes-catalyzed reaction proceeds on only one side of the planar PLP-substrate complex. However, in the amino acid racemase... 

Murakami et al. also examined the enantioselectivity of the catalyzed transamination reaction in a bilayer membrane [26]. They contrasted a system composed of a peptide lipid bearing an L-lysine residue (34), a hydrophobic pyridoxal derivative quaternized at the pyridyl nitrogen (37), and Cu(ii) ions. This system exhibited turnover behavior for... 

The most common acceptors of amino groups in transamination reactions are a-ketoglutarate, oxaloacetate, and pyruvate. Transamination reactions are readily reversible. Some amino acids, such as lysine, do not transaminate in the manner indicated in Equation (20.7). 

Lysine Does not transaminate Cadaverine Cadaverine is toxic and has odor of rotting flesh... 

The catabolism of lysine merges with that of tryptophan at the level of (3-ketoadipic acid. Both metabolic pathways are identical from this point on and lead to the formation of acetoacetyl-CoA (Figure 20.21). Lysine is thus ketogenic. It does not transaminate in the classic way. Lysine is a precursor of carnitine the initial reaction involves the methylation of e-amino groups of protein-bound lysine with SAM. The N-methylated lysine is then released proteolytically and the reaction sequence to carnitine completed. See Equation (19.6) for the structure of carnitine. 

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