A-Aminoadipate

Weber, P. L. Buck, D. R. Capillary Electrophoresis A Past and Simple Method for the Determination of the Amino Acid Composition of Proteins, /. Chem. Educ. 1994, 71, 609-612. This experiment describes a method for determining the amino acid composition of cyctochrome c and lysozyme. The proteins are hydrolyzed in acid, and an internal standard of a-aminoadipic acid is added. Derivatization with naphthalene-2,3-dicarboxaldehyde gives derivatives that absorb at 420 nm. Separation is by MEKC using a buffer solution of 50 mM SDS in 20 mM sodium borate. 

AH cephalosporins found in nature (Tables 1 and 2) have the D-a-aminoadipic acid 7-acyl side chain (21). AH of these compounds can be classified as having rather low specific activity. A substantial amount of the early work in the cephalosporin area was unsuccessfiiHy directed toward replacing the aminoadipic acid side chain or modifying it appropriately by fermentation or enzymatic processes (6,22). A milestone ia the development of cephalosporins occurred in 1960 with the discovery of a practical chemical process to remove the side chain to afford 7-ACA (1) (1). Several related processes were subsequendy developed (22,23). The ready avaHabHity of 7-ACA opened the way to thousands of new semisynthetic cephalosporins. The cephalosporin stmcture offers more opportunities for chemical modification than does that of penicillins There are two side chains that especiaHy lend themselves to chemical manipulation the 7-acylamino and 3-acetoxymethyl substituents. 

The first biosynthetic steps are two reactions that generate ACV from its constituent amino acids L-a-aminoadipic add, L-cysteine and L-valine. L-a-aminoadipic acid and L-cysteine are condensed by the enzyme AC synthetase and, in the next step, the resultant 8-(L-a-aminoadipyl)-L-cysteine is coupled with L-valine. In this step the configuration of L-valine is inverted to D-valine. 

Figure 6.9 Formation of isopenicillin N from its constituent amino acids. After condensation of L-a-aminoadipic acid with L-cysteine, L-valine is coupled. During this transformation, the configuration of the latter amino acid inverts to give D-valine.

Nocardicin C 3-Aminonocardicinic and a-aminoadipic acids Pseudomonas schuyikilliensis... 

This is Da-aminoadipic add. You will learn a little later in the chapter that the normal biosynthetic pathway of pendllin production involves the incorporation of L-a aminoadipic add. The product is called isopenidllin N. 

The building blocks for the biosynthesis of benzylpenicillin are three amino acids, a-aminoadipic acid, cysteine and valine, and PAA. The amino acids condense to a tripeptide, ring closure of which gives the penicillin ring structure with an cu-aminoadipyl side-chain, isopenicillin N. The side-chain is then displayed by a phenylacetyl group from PAA to give benzylpenicillin. 

A simple example is the tripeptide precursor of the penicillin antibiotics, called ACV, an abbreviation for S-(L-a-aminoadipyl)-L-cysteinyl-D-valine. The amino acid precursors for ACV are L-a-aminoadipic acid (an unusual amino acid derived by modification of L-lysine), L-cysteine, and L-valine (not o-valine). 

A number of antibiotics (cephalosporins P, N, C) were isolated from the products of fermentation of the fungus Cephalosporium acremonicum. The major component of the mixture is cephalosporin C, an amide, the acid part of which is a-aminoadipic acid, and amine part—7-aminocephalosporanic acid. 

The a is L-lysine, as in the case of piperidine, but the f3 is different. The /3 is a-aminoadipic acid 6-semialdehyde. The q> is L-pipecolic acid, which is synthesized in plants from piperideine-6-carboxylic acid. In the case of many other organisms, the obligatory intermedia (q>) is derived from the /3. The

ring structure. The indolizidine nucleus will be formed only in the synthesis of the x- The deep structmal change occms when

Claisen reaction with acetyl or malonyl CoA (Cra/mCoA) and the ring closme process (by amide or imine) to 1-indolizidinone, which is the x- The second obligatory intermedia ( k ) only has the indolizidine nucleus. 

Cephalosporins display an antibiotic mechanism of action identical to that of the penicillins. Cephalosporin C (Figure 1.14) is the prototypic natural cephalosporin and is produced by the fungus Cephalosporium acremonium. Most other members of this family are semi-synthetic derivatives of cephalosporin C. Chemical modification normally targets side-chains at position 3 (the acetoxymethyl group) or 7 (derived from D-a-aminoadipic acid). 

Following Scheme 4, L-a-aminosuberic acid can be obtained from iV-tosyI -L-gl utamic acid (5, n=2), upon protection of the a-carboxy and tosylamino groups as an oxazolidone 6, by extension of the side chain with the Amdt-Eistert method via the diazo ketone 7 by one methylene moiety in each cycle to produce in subsequent steps the L-a-aminoadipic acid [(5)-2-aminohexanedioic acid, 8, n = 2], L-a-aminopimelic acid [(5)-2-aminoheptanedioic acid, 8, n = 3] and finally L-a-aminosuberic acid [(5)-2-aminooctanedioic acid, 8, n = 4]J22 Treatment with HBr in AcOH was the method of choice for the acidolytic hydrolysis of the tosyl group. 23 ... 

Scheme 4 Synthesis of L-a-Aminosuberic Acid from A-Tosyl-i.-glutamic Acid (n = 2) via L-a-Aminoadipic (n = 3) and L-a-Aminopimelic Acid (n = 4) 22 ...

AASA a-aminoadipic semialdehyde, AdoHcy S-adenosylhomocysteine, AdoMet S-adenosylmethionine, Ala alanine, Arg arginine, alle alloisoleucine, Apo aminopiperidone, ASA argininosuccinate,... 

The essential amino acid lysine (2,5-diaminohexanoic acid) can be degraded via two pathways, viz. the so-called saccharopine pathway and the pipecolic acid (PA) pathway. Both pathways merge at the level of a-aminoadipic acid semialdehyde (AASA). It is generally accepted that the saccharopine pathway constitutes the major breakdown pathway. However, the PA pathway has attracted much attention since the discovery of the association between the presence of elevated PA levels and Zellweger syndrome almost 40 years ago. Mainly because the analysis of amino acids was the primary biochemical approach for studying presumed inborn errors of metabolism, PA in Zellweger syndrome was discovered even before it was realized that this disorder was based on a defect of peroxisomal functions. 

Lysine cannot be made at all by animals but is nutritionally essential. There are two distinct pathways for its formation in other organisms. Tire a-aminoadipate pathway (shown in Fig. 24-9) occurs in a few lower fungi, the higher fungi, and euglenids. 

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