Pyruvoyl amino acids

The complexes of four oxime analogs of amino acids (N-pyruvoyl amino acid oximes) with Bu2SnO were prepared. The ligands are coordinated to the tin centers by monodentate -COO , and oxime N atoms and Oh or Tbp species are formed.Similar studies were performed on the MeSn(IV)-SalGly (salycil-glycine) system. ... 

Chigira, Y., M. Masaki, and M. Ohta Syntheses and Reactions of N(Phenyl-pyruvoyl) Amino Acids. Bull. Chem. Soc. Jap. 42, 224 (1969). 

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 ... 

Huynh QK, EE Snell (1985) Pyruvoyl-dependent histidine decarboxylases. Preparation and amino acid sequences of the p chains of histidine decarboxylase from Clostridium perfringens and Lactobacillus buchneri. J Biol Chem 260 2798-2803. 

PTPS (6-Pyruvoyl Tetmhydropterin Synthase). 6-Pyruvoyl tetrahy-dropterin synthase catalyzes formation of tetrahydrobiopterin biosynthesis. Tetrahydrobiopterin is a cofactor for several important enzymes, such as aromatic amino acid hydroxylases and nitric oxide synthase (57). H. pylori protein HPAG1 0913 shares homology with members of the protein domain family PTPS. H. pylori protein shares poor sequence identity of 14% with the PTPS profile at an E-value of 10 10 and covers about 95% of the length of the profile. Fold recognition results also confirm the relationship between H. pylori protein and the PTPS protein domain family. A fold recognition algorithm ensures fitness of the H. pylori protein sequence on the three-dimensional structure of PTPS from... 

The quinone ring is derived from isochorismic acid, formed by isomerization of chorismic acid, an intermediate in the shikirnic acid pathway for synthesis of the aromatic amino acids. The first intermediate unique to menaquinone formation is o-succinyl benzoate, which is formed by a thiamin pyrophosphate-dependent condensation between 2-oxoglutarate and chorismic acid. The reaction catalyzed by o-succinylbenzoate synthetase is a complex one, involving initially the formation of the succinic semialdehyde-thiamin diphosphate complex by decarboxylation of 2-oxoglutarate, then addition of the succinyl moiety to isochorismate, followed by removal of the pyruvoyl side chain and the hydroxyl group of isochorismate. 

Ergotamine. LSA indicates the lysergic acid moiety. The dashed line indicates that the cleavage takes place between the a-nitrogen atom and the a-carbon atom of the amino acid involved, namely a-hydroxyalanine. This results in a pyruvoyl precursor of phenylalanine-proline lactam which can have structure 2 or 3. Structure 3 is that of pynoergotamine, a reference sample of which showed the same GC and MS behaviour as the above pyruvoyl precursor. However, this does not preclude structure 2 (which is more stable) for this precursor, but for which no reference sample was available. Structure 4 is the phenylalanine-proline lactam, which is obtained in two forms, namely L-phe-D-pro lactam and L-phe-L-pro lactam. 

Although most amino acid decarboxylases use PLP as a cofactor, a number of decarboxylases use covalently bound pyruvate instead (722, 123). The pyruvate-dependent enzyme consists of two types of chains. The pyruvoyl cofactor is formed by the cleavage of a Ser-Ser linkage in a single-chain precursor and is bound as an amide to the N-terminus of one polypeptide chain. 

The elimination of a CO2 molecule from the substrate catalyzed by decarboxylases requires the stabilization of a carbanionic intermediate, a task often performed by enzymatic cofactors. Indeed, decarboxylation reactions on ct-amino acids are catalyzed mainly by PLP-dependent enzymes, with a small fraction of reactions catalyzed by enzymes that use a pyruvoyl cofactor." PLP-dependent decarboxylases are largely widespread among both eukaryotes and prokaryotes where they participate in the biosynthesis of biological amines (e.g., dopamine, histamine, and serotonine) and polyamines. In addition, in prokaryotes, inducible PLP-dependent decarboxylases take part in the regulation of intracellular pH." ... 

The 1.25 A-crystal structure of the mouse SR in complex with NADP has been solved. The 261 amino acids of the monomer fold into a single domain a//3-structure. A seven-stranded parallel /3-sheet in the center of the molecule is sandwiched by two arrays of three a-helices. The association of two monomers to the active homodimeric SR leads to the formation of a four-helix bundle (Figure 13). Owing to the two-folded crystallographic symmetry of the homodimeric molecule, the parallel /3-sheets in monomer A is in an antiparallel orientation relative to the /3-sheet of monomer B enclosing an angle of 90°. The overall dimensions of the SR dimer are 40 A X 50 A x 80 A. The two substrate pockets bind sepiapterin (or 6-pyruvoyl-tetrahydropterin 42), and the cofactor NADP/NADPH from opposite sides to the enzyme. 

The carbonyl functional group provides an electrophilic site for nucleophilic attack. As none of the naturally occurring amino acids contains a ketone or aldehyde moiety, it is not possible for a protein-bound carbonyl group to be present at an enzyme active site, unless it is provided by a cofactor. The most commonly seen reactive carbonyl group in enzymes is that provided by the pyridoxal phosphate cofactor which is derived from vitamin B6." The carbonyl serves as a site for covalent adduct formation with a nucleophilic substrate, often an amine or the amino group of amino acid substrates. An alternative strategy for introduction of a reactive carbonyl at an enzyme active sight has been described for a class of enzymes that possess a covalent pyruvoyl cofactor. 

Pyruvoyl cofactor is derived from the posttranslational modification of an internal amino acid residue, and it does not equilibrate with exogenous pyruvate. Enzymes that possess this cofactor play an important role in the metabolism of biologically important amines from bacterial and eukaryotic sources. These enzymes include aspartate decarboxylase, arginine decarboxylase," phosphatidylserine decarboxylase, . S-adenosylmethionine decarboxylase, histidine decarboxylase, glycine reductase, and proline reductase. ... 

Figure 3 compares the proficiencies (kcat/K]v[/kun) of ODCase, several other enzyme decarboxylases [2], and some antibody decarboxylases [3]. The proficiencies of the decarboxylase enzymes, including a variety of amino acid decarboxylases, are nearly equal. Many decarboxylases employ iminium intermediates formed by reaction of an amino acid with a cofactor such as pyruvoyl or pyridoxal, or by reaction of a -keto ester with an active-site lysine residue. These intermediates have been found to be so reactive that the... 

Figure 1.36 Pyruvoyl-dependent decarboxylation of amino acids.

Fig. 1.1. Biosynthesis and regeneration of tetrahydrobiopterin including possible metabolic defects and catabolism of phenylalanine. l.l=phenylalanine-4-hydroxylase (PAH) 1.2/1.6 = GTP cyclohydrolase I (GTPCH), 1.3 = 6-pyruvoyl-tetra-hydropterin synthase (PTPS), 1.4 = dihydropteridine reductase (DHPR), 1.5 = pterin-4a-carbinolamine dehydratase (PCD), 1.7 = sepiapterin reductase SR, carbonyl reductase (CR), aldose reductase (AR), dihydrofolate reductase (DHFR), aromatic amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), nitric oxide synthase (NOS). Pathological metabolites used as specific markers in the differential diagnosis are marked in squares. n.e.=non-enzymatic...

N-Trifluoroacetylation of amino-acids and peptides is easily carried out by using ethyl trifluoroacetate in methanol containing triethylamine. A way to N-formylate a-amino-acid esters with formic anhydride has been reported which involves an improved method for the in situ generation of the latter. The oxazole-5-one (172) is a useful reagent for converting methyl esters of a-amino-acids into their N -pyruvoyl derivatives. ... 

Bach, R.D. and Canepa, C. (1997) Theoretical model for pyruvoyl-dependent enzymatic decarboxylation of a-amino acids. J. Am. Chem. Soc., 119, 11725-11733. 

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