Aminopeptidase and

T-cell activating antigen although the aminopeptidase and immunological functions do not appear to interfere with each other. 

Asano, Y. and Yamaguchi, S. (2005) Dynamic kinetic resolution of amino acid amide catalyzed by D-aminopeptidase and a-amino-e-caprolactam racemase. Journal of the American Chemical Society, 127 (21), 7696-7697. 

Non-corrin cobalt has a number of interesting applications in the chemical industry, for example in the hydroformylation (OXO) reaction between CO, H2 and olefins. A number of non-corrin Co-containing enzymes have been described, including methionine aminopep-tidase, prolidase, nitrile hydratase and glucose isomerase. We describe the best characterized of these, namely the E. coli methionine aminopeptidase, a ubiquitous enzyme, which cleaves N-terminal methionine from newly translated polypeptide chains. The active site of the enzyme (Figure 15.13) contains two Co(II) ions that are coordinated by the side-chain atoms of five amino acid residues. The distance between the two Co2+ is similar to that between the two Zn2+ atoms in leucine aminopeptidase, and indeed the catalytic mechanism of methionine aminopeptidase shares many features with other metalloproteases, in particular leucine aminopeptidases. 

See Section IV.1 for alternative methods of chiral resolution. Partial chemical hydrolysis of proteins and peptides with hot 6 M HC1, followed by enzymatic hydrolysis with pronase, leucine aminopeptidase and peptidyl D-amino acid hydrolase, avoids racemiza-tion of the amino acids281. The problems arising from optical rotation measurements of chiral purity were reviewed. Important considerations are the nonideal dependence of optical rotation on concentration and the effect of chiral impurities282. 

Increased permeability is just one prerequisite in the development of useful peptide prodrugs. Another condition is that efficient bioactivation must follow absorption. Mucosal cell enzymes able to hydrolyze peptides include exopeptidases such as aminopeptidases and carboxypeptidases, endopepti-dases, and dipeptidases such as cytosolic nonspecific dipeptidase (EC 3.4.13.18), Pro-X dipeptidase (prolinase, EC 3.4.13.4), and X-Pro dipeptidase (prolidase, EC 3.4.13.9). For example, L-a-methyldopa-Pro was shown to be a good substrate for both the peptide transporter and prolidase. This dual affinity is not shared by all dipeptide derivatives, and, indeed, dipeptides that lack an N-terminal a-amino group are substrates for the peptide transporter but not for prolidase [29] [33] [34],... 

The brush border enzymes in the intestine play a major role in peptide hydrolysis. Thus, both aminopeptidase and endopeptidase activities were detected with [Leu5]enkephalin as the substrate [146],... 

The pattern and efficiency of hydrolysis of [Leu5]enkephalin, like that of any peptide, depends to a large extent on its compartmentalization. In other words, the qualitative and quantitative aspects of its degradation vary considerably as a function of species, tissue, and concentration profile. Thus, hydrolysis of [Leu5] enkephalin in rat brain is catalyzed mainly by aminopeptidase, ACE, and neprilysin, in rat lungs by aminopeptidase and ACE, and in rat plasma by aminopeptidase, dipeptidyl peptidase III, and ACE [171][172],... 

This zinc-dependent enzyme [EC 3.4.11.1], also referred to as cytosol aminopeptidase, leucyl aminopeptidase, and peptidase S, catalyzes the hydrolysis of a terminal peptide bond such that there is a release of an N-terminal amino acid, Xaa-Xbb-, in which Xaa is preferably a leucyl residue, but may be other aminoacyl residues including prolyl (although not arginyl or lysyl). Xbb may be prolyl. In addition, amino acid amides and methyl esters are also readily hydrolyzed, but the rates with arylamides are exceedingly slow. The enzyme is activated by heavy metal ions. 

Supports the activity of these proteases, including trypsin, chy-motrypsin, and several aminopeptidases and carboxypeptidases. 

Murphy, A., Peer, W.A., and Taiz, L., Regulation of auxin transport by aminopeptidases and endogenous flavonoids, Planta, 211, 315, 2000. 

The flavonoids fisetin and genistein exhibit antiangiogenic activity as evaluated in in vivo studies [279]. Flavonoids may also exert a limiting effect on tumor metastasis by way of their inhibitory activity on proteolytic enzymes such as trypsin, leucine aminopeptidase and other... 

Leucine Aminopeptidase and Other N-Terminal Exopeptidases Robert J. DeLange and Emil L. Smith... 

Various peptide Michael acceptors have been described as a new class of inactivators for cysteine proteases. 5-7 The carbonyl group of the scissile peptide bond in the substrate is replaced by a nucleophile trapping moiety such as a vinylogous structure. An amino acid vinyl sulfone, l-(methylsulfonyl)-4-phenylbut-l-en-3-amine [H2NCH(Bzl)CH=CHS02Me] and a dipeptide derivative, Gly-HNCH(Bzl)CH=CHS02Me have both been prepared as inhibitors of cysteine proteases, leucine aminopeptidase and dipeptidyl peptidase I, respectively.1 5 A series of peptide vinyl sulfones has been synthesized as potent inhibitors for different cysteine proteases. 1A8 ... 

Found to be subject to metal ion catalysis, but the discovery by Kroll in 1952 that the hydrolysis af a-amino acid esters was catalyzed by metal ions stimulated considerable interest in the area. Many of these reactions can be considered as simple model systems for such metalloenzymes as arboxypeptidase A, leucine aminopeptidase and glycylglycine dipeptidase.25... 

Sangadala, S., et al. 1994. A mixture of Manduca sexta aminopeptidase and phosphatase enhances Bacillus thuringiensis insecticidal CrylA(c) toxin binding and 86Rb(+)-K+ efflux in vitro. J Biol... 

This methodology was employed in a short synthesis of bestatin 26 (Scheme 2.11) [24] which acts as a potent inhibitor of aminopeptidase and prolyl endopepti-dase. 

Martinez, J., and F. Azam. 1993. Periplasmic aminopeptidase and alkaline phosphatase activities in a marine bacterium Implications for substrate processing in the sea. Marine Ecology Progress Series 92 89-97. 

As a synthetic application to biologically active compounds, eq. 8.19a shows the preparation of nucleoside antibiotics (44a) and (44b). Tyromycin (45) inhibits the leucine and cysteine aminopeptidases, and it can be prepared in good yield from the photolytic treatment of the Af-acyloxy diester with citraconic anhydride, followed by silica gel treatment, as shown in eq. 8.19b [55-60]. Other synthetic applications using intra- and intermolecular tandem reactions were also studied [61, 62]. 

Many biologically active secreted peptides are also amidated at their carboxyl terminal, and acetylated at their amino-terminal. The consequences of these modifications are (a) to reduce the susceptibility of these peptides to degradative actions of extracellular aminopeptidases and carboxypeptidases after their secretion and (b) to influence the biological activity of the peptides. Corticotropin-releasing factor, gastrin, cholecystokinin and vasopressin require the C-terminal amide for full activity [54—56]. Acetylation of the N-terminus of a-MSH is necessary for activity, whereas acetylation of /3-endorphin inhibits its opioid activity [57], The enzymes responsible for acetylation have been identified from bovine and rat intermediate lobes [57] and enzymes with a-amidation activity have been reported in preparations of pituitary secretory granules [54,55]. 

The N-Carboxy-Amino Acid Anhydride Method. Since the isopeptide bond of e-methionyllysine was hydrolyzed readily by intestinal aminopeptidase and the released amino acid was biologically available, we decided to further increase the amount of covalently attached methionine through a polymerization reaction. The most suitable amino acid derivative for this approach is the N-carboxyanhydride or Leuchs anhydride. 

Interestingly, compounds which have been investigated for their penetration-enhancing effect at the absorbing membrane have also been shown to decrease the metabolism of certain peptides. By denaturing leucine aminopeptidase and preventing enzyme-substrate complex formation, the bile salt sodium glycocholate has been shown to protect insulin from proteolysis in the rat nasal mucosa. 

Serum creatinine and BUN, the most common indicators of renal function used in both clinical and preclinical safety laboratory panels, are relatively insensitive markers of injury, particularly for the renal tubules. Urinary measurements of alanine aminopeptidase and A-acetyl-beta-D-glucosaminidase and kidney injury molecule-1 (KIM-1) can provide much more sensitivity when nephrotoxicity is a potential safety concern [28,29], These are also suitable for safety monitoring in early-phase human trials if preclinical studies validate such use to monitor product nephrotoxicity. 

Pepsin and the pancreatic proteases catalyze the conversion of dietary protein to peptides and amino acids. The aminopeptidases and the dipeptidases in the intestinal mucosa almost complete the hydrolysis of the peptides to amino acids, but some peptides, especially those containing glutamate, pass into the gut mucosal cells with the free amino acids. The aminopeptidases remove amino acids from the N-terminus of a peptide. 

Most biochemical assays used to determine the potency of inhibitors against (1) aminopeptidases and (2) endopeptidases with minor contributions to the substrate binding efficiency by the S site are based on the measurement of fluorescence intensity (FI). The FI readout principle is shown in Figure 2.2. The dynamic range of the FI readout basically scales with the fluorescence quantum yield, that is, the efficiency of fluorescence emission of the dye label. For the FI readout, peptide substrates with fluorogenic groups such as acetylmethoxycoumarin (AMC), 7-amino-4-trifluoromethyl... 

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