P-Alanines

Fig. 10. Sequences (see Table 1) of betabeUins. In each case, only one-half of the P-sandwich is shown. The dimer is formed from identical monomeric sets of four P-strands. In the pattern sequence, e is for end, p is for polar residue, n is for nonpolar residue, and t and r are for turn residues. Lower case f is iodophenyialanine lower case a, d, k, and p are the D-amino acid forms of alanine, aspartic acid, lysine, and proline, respectively B is P-alanine (2,53,60,61).

R)-Pantothenic acid (1) contains two subunits, (R)-pantoic acid and P-alanine. The chemical abstract name is A/-(2,4-dihydroxy-3,3-dimethyl-l-oxobutyl)-P-alanine (11). Only (R)-pantothenic acid is biologically active. Pantothenic acid is unstable under alkaline or acidic conditions, but is stable under neutral conditions. Pantothenic acid is extremely hygroscopic, and there are stabiUty problems associated with the sodium salt of pantothenic acid. The major commercial source of this vitamin is thus the stable calcium salt (3) (calcium pantothenate). 

R)-Calcium pantothenate (3) is prepared by condensing (R)-pantolactone (9) with P-alanine (10) in the presence of base, followed by treatment of the sodium salt (11) with calcium hydroxide. 

The metabohcaHy active form of pantothenic acid is coen2yme A. Pantothenic acid is produced only by microorganisms, starting from (R)-pantoate (22) and P-alanine. (R)-Pantoate is synthesi2ed by a set of en2ymatic reactions, as follows (63,64) ... 

Aspartic acid decarboxylase cataly2es the decarboxylation of asparatic acid to yield P-alanine (10), a precursor for the biosynthesis of pantothenic acid (67). FiaaHy, (R)-pantothenic acid is obtaiaed by coupling P-alaniae (10) with (R)-pantoate (22) ia the presence of pantothenate synthetase ... 

RS- P-Aminoisobutyric acid (a-methyl-P-alanine) [10569-72-9] M 103.1, m 176-178 , 178-180 , 181-182 , R -(-)- isomer [144-90-1] m 183 , [a] -21 (c 0.43, HjO), pKes,(,) 3.7, pKEst(2) 10.2. Colorless prisms from hot H O, were powdered and dried in vacuo. The purity is checked by paper chromatography (Whatman 1) using ninhydrin spray to visualise the amino acid Rp values in 95% MeOH and n-PrOH/5N HCOOH (8 2) are 0.36 and 0.50 respectively. [Kupiecki and Coon Biochem Prep 7 20 7960 Pollack J Am Chem Soc 65 1335 7943.] The R-enantiomer, isolated from iris bulbs or human urine was crystd from H2O and sublimed in vacuo [Asen et al. J Biol Chem 234 343 7959]. The RS-hydrochloride was recrystd from EtOH/Et20 m 128-129 , 130° [Bbhme et al. Chem Ber92 1258, 1260, 1261 7959]. 

R-(+)-Pantothenic acid sodium salt (7V-[2,4-dihydroxy-3,3-dimethylbutyryl] P-alanine Na salt) [867-81-2] M 241.2, [aJ +27.1 (c 2, H2O), pK 4.4 (for free acid). Crystd from EtOH, very hygroscopic (kept in sealed ampoules). The free acid is a viscous hygroscopic oil with [a] +37.5 (c 5, H2O), easily destroyed by acids and bases. 

Recently the Bohlmann-Rahtz synthesis has received greater attention. Baldwin has employed this method for the construction of heterocyclic substituted a-amino acids. Exposure of alkynyl ketone 39 to 3-aminocrotoyl ester 40 resulted in the Michael product 41. Thermolysis then gave rise to the desired pyridyl-P-alanines 42. 

CN (R)-A-(2,4-dihydroxy-3,3-dimethyl-l-oxobutyl)-P-alanine monosodium salt... 

N-(3-ethoxy-3-oxopropy])-A -(phenylmethyl)-P-alanine ethyl ester... 

C7H4N2O2 619-24-9) see Tazanolast A -(4-nitrobenzoyl)-p-alanine (CJ0H10N2O3 59642-21-6) see Balsalazide sodium /7-nitrobenzoyl chloride... 

P-Alanine, a metabolite of cysteine (Figure 34-9), is present in coenzyme A and as P-alanyl dipeptides, principally carnosine (see below). Mammalian tissues form P-alanine from cytosine (Figure 34-9), carnosine, and anserine (Figure 31-2). Mammalian tissues transami-nate P-alanine, forming malonate semialdehyde. Body fluid and tissue levels of P-alanine, taurine, and... 

The P-alanyl dipeptides carnosine and anserine (A -methylcarnosine) (Figure 31-2) activate myosin ATPase, chelate copper, and enhance copper uptake. P-Alanyl-imidazole buffers the pH of anaerobically contracting skeletal muscle. Biosynthesis of carnosine is catalyzed by carnosine synthetase in a two-stage reaction that involves initial formation of an enzyme-bound acyl-adenylate of P-alanine and subsequent transfer of the P-alanyl moiety to L-histidine. 

Hydrolysis of carnosine to p-alanine and L-histidine is catalyzed by carnosinase. The heritable disorder carnosinase deficiency is characterized by carnosinuria. 

Decarboxylation of histidine forms histamine, and several dipeptides are derived from histidine and P-alanine. 

Unlike the end products of purine catabolism, those of pyrimidine catabolism are highly water-soluble COj, NH3, P-alanine, and P-aminoisobutyrate (Figure 34-9). Excretion of P-aminoisobutyrate increases in leukemia and severe x-ray radiation exposure due to increased destruction of DNA. However, many persons of Chinese or Japanese ancestry routinely excrete P-aminoisobutyrate. Humans probably transaminate P-aminoisobutyrate to methylmalonate semialdehyde, which then forms succinyl-CoA (Figure 19-2). 

Since the end products of pyrimidine catabolism are highly water-soluble, pyrimidine overproduction results in few clinical signs or symptoms. In hypemricemia associated with severe overproduction of PRPP, there is overproduction of pyrimidine nucleotides and increased excretion of p-alanine. Since A, A -methyl-ene-tetrahydrofolate is required for thymidylate synthesis, disorders of folate and vitamin Bjj metabofism result in deficiencies of TMP. 

We used diethanolamine (DEA), 2,3-diaminopropionic acid monohydrochloride (DAPA), P-alanine and taurine, as absorbents of CO2 without further purification. An equimolar... 

Fig. 2. Agents controlling the opening of Cl -channels. The structural formula, the name, the respeetive Cl -channel, and an appropriate reference are provided. (A) Note the similarity of GABA, taurine, and P-alanine. Note also that DPC and its analogues such as NPPB contain a -alanine backbone. (B) The structure of torasemide comes close to both DPC and furosemide or buraetanide. It blocks the Na ZCPK" -cotransporter with very high affinity and with lesser affinity also the TAL-Cl -channel. Note that IAA-94 is related to phenoxyaeetic acids (e.g., ethacrynic acid). Amidine is related to IAA-94 but it has a positive net charge. Amidine as well as IAA-94 block the ICOR channel at around lO mol/1 [63].

Substantial attention has been devoted to the metabolism of 5-fluorouracil and related compounds. For example, F NMR was used successfully both in cell extracts and in whole mycelia to elucidate anabolic reactions involving pyrimidine nucleotides and degradation to a-fluoro-p-alanine in the fungus Nectria haematococca (Parisot et al. 1989,1991). 

Fluoro-2 -deoxyuridine has been extensively used in studies of the mechanism of action of thymidylate synthase, and 5-fluorouracil is an anticancer drug that has provided a lead to the development of others. The metabolism of 5-fluorouracil by the ascomycete fungus Nectria haematococca has been studied using F NMR (Parisot et al. 1991). a-Fluoro-P-alanine (2-fluoro-3-aminopropionate) was produced (Figure 10.27), while 5-fluorouridine-5 -mono-, di-, and triphosphate were found in acid extracts of the mycelia, and the 2 - and 3 -monophosphates were recovered from RNA. 

Many reports confirm notable reductions in reaction times when carrying out reactions under micro flow conditions. Concerning p-dipeptide synthesis, for example, a comparison between batch and micro-reactor processing was made for the reaction of Dmab-P-alanine and Fmoc-i-P-homophenylalanine [158]. While the micro reactor gave a 100% yield in 20 min, only about 5% was reached with the batch method. Even after 400 h, only 70% conversion was achieved. 

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