Arginine intermediates

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

Cleavage occur s at the scissile bond. Residues in the substrate towards the N-terminus are numbered PI, P2, P3, etc, whereas residues towards the C-terminus are numbered PI, P2, P3 etc. Cleavage occurs between PI and P1. For a peptidase with limited specificity, only the residue in PI or PI is important for specificity. A peptidase with an extended substrate binding site will have a preference for residues in other positions. For example cathepsin L prefers substrates with phenylalanine in P2 and arginine in PI. However, this is a preference only, and cathepsin L cleaves substrates after other amino acids. Caspase-3 has a preference for Asp in both P4 and PI, but it is unusual for substrate specificity to extend much further from the scissile bond. The peptidase with the most extended substrate specificity may be mitochondrial intermediate peptidase that removes an octopeptide targeting signal from the N-terminus of cytoplasmically synthesized proteins that are destined for import into the mitochondrial lumen. 

NO synthase catalyzes a five-electron oxidation of an amidine nitrogen of arginine. L-Hydroxyarginine is an intermediate that remains tighdy bound to the en-... 

Species of Pseudomonas can utilize the a,(i)-diamines putrescine, spermidine, and spermine as sources of carbon and nitrogen, and putrescine can be produced from the secondary amine spermidine together with 1,3-diaminopropane (Dasu et al. 2006). Putrescine (1,4-diaminobutane) is an intermediate in the arginine decarboxylase (ADC) pathway of L-arginine degradation, which is described later, and can be degraded, by two pathways ... 

FIGURE 22.4 Mechanism of nitric oxide and L-citrulline production by NO synthases through the intermediate formation of iV-hydroxyl-L-arginine. 

James, S.L. andGlaven, J., Macrophage cytotoxicity against schistosomula of Schistosoma mansoni involves arginine-dependent production of reactive nitrogen intermediates, J. Immunol., 143, 4208,1989. 

Endogenous NO is produced almost exclusively by L-arginine catabolism to L-citrul-line in a reaction catalyzed by a family of nitric oxide synthases (NOSs) [3]. In the first step, Arg is hydroxylated to an enzyme-bound intermediate "-hydroxy-1.-arginine (NHA), and 1 mol of NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) and O2 are consumed. In the second step, N H A is oxidized to citrulline and NO, with consumption of 0.5 mol of NADPH and 1 mol of 02 (Scheme 1.1). Oxygen activation in both steps is carried out by the enzyme-bound heme, which derives electrons from NADPH. Mammalian NOS consists of an N-terminal oxy-... 

P. L., Wiseman, J. N. omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine,J. Biol. Chem. 266 (1991), p. 6259-6263... 

The mechanism that is consistent with biochemical, enzymological and structural data involves binding of arginine, in which the side-chain of Glu277 plays an important role, attack of the nucleophilic metal-bridged hydroxyl ion, formation of a neutral, tetrahedral intermediate which is stabilized by the dinuclear Mn(II) centre, and finally proton transfer from Hisl41, followed by release of the two products (Figure 16.5). 

L Zervas, M Winitz, JP Greenstein. Studies on arginine peptides. I. Intermediates in the synthesis of N-terminal and C-terminal arginine peptides, (benzyl esters) J Org Chem 22, 1515, 1957. 

Using a spectrophotometric method, McMillan and Masters93 obtained evidence that bNOS contained a heme group that reacted with L-arginine and with iVG-hydroxy-L-arginine (an intermediate) and /VG-rncthyl-i.-arginine (an inhibitor). They therefore concluded that the heme was an oxygen donor. 

An anomaly associated with citrulline that became evident when detailed kinetic studies were made in the 1950s (R.B. Fisher and J.R. Bronk) was the irreproducibility of its catalytic activity in liver slices on the formation of urea, despite the clear evidence from Ratner and Petrack of its importance in arginine synthesis. Initially the discrepancy in catalytic activity between ornithine and citrulline was ascribed to the possible impermeability of the liver cell plasma membrane to the latter intermediate, a hypothesis which was rapidly disproved experimentally. Only recently has it been shown that ornithine transcarbamylase is clearly associated with the ornithine/... 

---