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Enzyme alanine racemase

Inhibits the enzymes alanine racemase and D-alanyl-D-alanyl synthetase that are responsible for producing the dipeptide D-alanyl-D-alanine, a precursor of the pentapeptide chain in cell wall formation. It is believed that the rigid structure of the isoxazole ring gives the drug a better chance of binding to the enzyme than the more flexible structure of D-alanine. [Pg.137]

A simple procedure was established for the synthesis of various D-amino adds by means of four types of thermostable enzymes alanine racemase, D-amino acid aminotransferase 49, 501, L-alanine dehydrogenase 51, and formate dehydrogenase (Fig. 17-4) 171. The commercial preparation of formate dehydrogenase from Candida boidinii used by Wichmanri et al. 38 is not sufficiently stable. However, Galkin et al.1521 doned and expressed the gene of thermostable formate dehydrogenase in E. coli. [Pg.1287]

Table 17-2. Synthesis of D-amino acids from a-keto acids by combination of four purified enzymes alanine racemase, L-alanine dehydrogenase, formate dehydrogenase, and D-amino acid aminotransferase. Table 17-2. Synthesis of D-amino acids from a-keto acids by combination of four purified enzymes alanine racemase, L-alanine dehydrogenase, formate dehydrogenase, and D-amino acid aminotransferase.
Proton transfer to the imine carbon of the achiral intermediate gives equal amounts of both enantiomers of the PLP imine. The equation illustrates the racemization of L-alanine, which is catalyzed by the PLP-dependent enzyme alanine racemase. Because D-alanine is an essential component of bacterial cell walls, there is considerable interest in designing inhibitors of alanine racemase as potential antibacterial drugs. [Pg.1134]

Turning to l-AAO, Pantaleone s industrial research group have reported" on the properties and use of an l-AAO from Proteus myxofaciens, overexpressed in Escherichia coli This l-AAO, unusually, appears not to produce H2O2 in the catalytic reaction, thus making the addition of catalase unnecessary. The enzyme has a broad specificity, with a preference for nonpolar amino acids. This l-AAO was used in conjunction with a D-amino acid transaminase (d-AAT) and an alanine racemase (AR) to allow an efficient conversion of L-amino acid in to D-amino acid (Scheme 4). [Pg.75]

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]. [Pg.7]

The reversal of this process could potentially occur with reprotonation from either face of the C=N double bond, and a mixture of aldimines would result, leading to generation of a racemic amino acid. This accounts for the mode of action of PLP-dependent amino acid racemase enzymes. Of course, the enzyme controls removal and supply of protons this is not a random event. One important example of this reaction is alanine racemase, employed by bacteria to convert L-alanine into o-alanine for cell-wall synthesis (see Box 13.12). [Pg.600]

Cycloserine (Fig- 4) is produced by several species of Streptomyces. One of the basic glycosyl components of the bacterial cell wall, n-acetyl-muramic acid (the product of Mur A and MurB), is modified by the addition of the first three amino acids sequentially by MurC, MurD and MurE enzymes. A dipeptide, D-alanyl-D-alanine is then added to make the pentapeptide. In bacteria, L-alanine is the native form and it is converted to D-alanine form by alanine racemase (Air). Two D-alanines are joined by D-ala-D-ala ligase (DdlA) to synthesize the dipeptide. Cycloserine resembles the substrate for Air and Ddl and inhibits their respective reactions in stage I of the peptidoglycan biosynthesis (Fig. 2). [Pg.360]

PLP-dependent enzymes catalyze the following types of reactions (1) loss of the ce-hydrogen as a proton, resulting in racemization (example alanine racemase), cyclization (example aminocyclopropane carboxylate synthase), or j8-elimation/replacement (example serine dehydratase) (2) loss of the a-carboxylate as carbon dioxide (example glutamate decarboxylase) (3) removal/replacement of a group by aldol cleavage (example threonine aldolase and (4) action via ketimine intermediates (example selenocysteine lyase). [Pg.590]

Inhibition of pyridoxal phosphate enzymes by fluoroalanines has been widely studied. Among the numerous examples, alanine racemase, tyrosine phenol... [Pg.151]

Fluoro amino acids have been incorporated into peptides, in order to ease the transport or reduce the systemic toxicity. Thus, trifluoroalanine, a powerful inhibitor of alanine racemase, is an essential enzyme for the biosynthesis of the cell wall of bacteria. It has a low antibiotic activity because of its very poor transport. In order to facilitate this transport, the amino acid has been incorporated into a peptide. This delivery allows a reduction of the doses, and thus the toxicity of the treatment is lowered.3-FIuorophenylaIanine (3-F-Phe) is a substrate of phenylalanine hydroxylase, which transforms it into 3-F-Tyr. 3-F-Tyr has a high toxicity for animals, due to its ultimate metabolization into fluorocitrate, a powerful inhibitor of the Krebs cycle (cf. Chapter 7). 3-F-Phe has a low toxicicity toward fungus cells, but when delivered as a tripeptide 3-F-Phe becomes an efficient inhibitor of the growth of Candida albicans. This tripeptide goes into the cell by means of the active transport system of peptides, where the peptidases set free the 3-F-Phe. ... [Pg.171]

Very detailed studies on the inhibition of alanine racemase by fluoroalanines have been conducted. This enzyme catalyzes the racemization of alanine to provide D-alanine, which is required for synthesis of the bacterial wall. This work has demonstrated that a more complex process than that represented in Figure 7.47 could intervene. For instance, in the case of monofluoroalanine, a second path (Figure 7.48, path b) occurs lysine-38 of the active site can also attack the Schiff base PLP-aminoacrylate that comes from the elimination of the fluorine atom. This enamine inactivation process (path b) has been confirmed by isolation and identification of the alkylation compound, after denaturation of the enzyme (Figure 7.48). ... [Pg.257]

Another enzyme-activated inhibitor is the streptomyces antibiotic D-cycloserine (oxamycin), an antitubercular drug that resembles D-alanine in structure. A potent inhibitor of alanine racemase, it also inhibits die non-PLP, ATP-dependent, D-alanyl-D-alanine synthetase which is needed in the biosynthesis of die peptidoglycan of bacterial cell walls. [Pg.739]

The process of racemization is important in the survival and growth of living cells and is catalyzed by a group of enzymes called racemases. Alanine racemase. for example, is able to convert n-alanine to DL-alanine if a suitable alpha keto acid is also present. In this reaction the asymmetry of the alpha-carbon atom of alanine is lost as the amino acid is converted to the keto acid and back. This process is analogous to the well-known process of transamination in which racemization seldom occurs. [Pg.1405]

Alanine racemase, as another PLP-dependent enzyme, is a bacterial enzyme used to create D-alanine from L-alanine for incorporation into the bacterial cell wall. Its role is to act as an electron sink to stabilize carbanionic intermediates generated in enzymatic catalysis. [Pg.277]

K Hoffmann, E Schneider-Scherzer, H Kleinkauf, R Zocher. Purification and characterization of eucaryotic alanine racemase acting as key enzyme in cyclosporin biosynthesis. J Biol Chem 17 12710-12714, 1994. [Pg.496]

Fig. 8.1 Linear alignment of the protein sequences of alanine racemases from B. subtilis, B. stearothermophilus, S. typhimurium dadB, and S. typhimurium air. The sequences of four alanine racemases were aligned by introducing gaps (hyphens) to maximize identities. Common residues among the four ( ) and three ( ) enzymes are shown below. The active-site lysyl residue is indicated with an asterisk. The vertical arrow shows the position where the limited proteolysis occurs. (Reproduced with permission from Tanizawa el al., Biochemistry, 27, 1311 (1988)). Fig. 8.1 Linear alignment of the protein sequences of alanine racemases from B. subtilis, B. stearothermophilus, S. typhimurium dadB, and S. typhimurium air. The sequences of four alanine racemases were aligned by introducing gaps (hyphens) to maximize identities. Common residues among the four ( ) and three ( ) enzymes are shown below. The active-site lysyl residue is indicated with an asterisk. The vertical arrow shows the position where the limited proteolysis occurs. (Reproduced with permission from Tanizawa el al., Biochemistry, 27, 1311 (1988)).
Alanine racemase of B. stearothermophilus consists of two identical subunits, whereas both DadB and air enzymes of Salmonella typhimurium and the Streptococcusfaecalis enzyme occur in a form of monomer. Toyama et al.14) examined whether the monomeric form of the B. stearothermophilus enzyme is catalytically active. They studied the guanidine HC1-induced subunit dissociation and unfolding of the enzyme by fluorescence and absorption spectroscopies, circular dichroism (CD) analysis, and gel filtration.I4) The overall process was found to be reversible more than 75% of the original activity was recovered by decreasing the denaturant concentration. [Pg.150]

Fig. 8.4 Schematic representation of the wild-type and fragmentary alanine racemase. Only several of the relevant amino acid residues in the terminal portions are shown. The C-terminus of the N-terminal part of the fragmentary enzyme contains five extra amino acids residues. (Reproduced with permission from Toyama etal., J. Biol. Chem., 266, 13637 (1991)). Fig. 8.4 Schematic representation of the wild-type and fragmentary alanine racemase. Only several of the relevant amino acid residues in the terminal portions are shown. The C-terminus of the N-terminal part of the fragmentary enzyme contains five extra amino acids residues. (Reproduced with permission from Toyama etal., J. Biol. Chem., 266, 13637 (1991)).
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... [Pg.155]


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See also in sourсe #XX -- [ Pg.1113 , Pg.1139 , Pg.1166 ]




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