Serine reaction steps

Absolute configurations of the amino acids are referenced to D- and L-glyceraldehyde on the basis of chemical transformations that can convert the molecule of interest to either of these reference isomeric structures. In such reactions, the stereochemical consequences for the asymmetric centers must be understood for each reaction step. Propose a sequence of reactions that would demonstrate that l( —)-serine is stereochemically related to l( —)-glyceraldehyde. 

The catalytic mechanism of serine proteinases. Two protons are shown in flight at each reaction step, as is probably the case with specific substrates non-specific substrates appear to react with the operation of only one-proton catalysis (Elrod et al., 1980)... 

OPs and CMs are acylating inhibitors (ABs) of AChE and BuChE. Cholinesterases react with A6 compounds in the same way as they react with substrates that is, they acylate the hydroxyl group of serine in the catalytic site. However, there is a significant quantitative difference between substrates and AB compounds in the rates of the individual reaction steps. In the reaction with. substrates, acylation and deacylation of the serine is very fast, whereas AB compounds quickly acylate the enzyme but very slowly deacylale from the enzyme, particularly when AB is an OP. The enzyme therefore stays acylaled by AB compounds for a long time and cannot hydrolyze substrates during that time. Consequently, OP and CM compounds are inhibitors of cholinesterases. 

The several reaction steps in the biosynthesis of serine can be written schematically as given in Eqs. (1-3). 

The reaction between esterase and phosphorus inhibitor (109) is bimolecular, of the weU-known S 2 type, and represents the attack of a nucleophilic serine hydroxyl with a neighboring imida2ole ring of a histidine residue at the active site, on the electrophilic phosphorus atom, and mimics the normal three-step reaction that takes place between enzyme and substrate (reaction ). 

The first domain of one subunit of the fatty acid synthase interacts with the second and third domains of the other subunit that is, the subunits are arranged in a head-to-tail fashion (Figure 25.9). The first step in the fatty acid synthase reaction is the formation of an acetyl-O-enzyme intermediate between the acetyl group of an acetyl-CoA and an active-site serine of the acetyl trails-... 

The metabolic breakdown of triacylglycerols begins with their hydrolysis to yield glycerol plus fatty acids. The reaction is catalyzed by a lipase, whose mechanism of action is shown in Figure 29.2. The active site of the enzyme contains a catalytic triad of aspartic acid, histidine, and serine residues, which act cooperatively to provide the necessary acid and base catalysis for the individual steps. Hydrolysis is accomplished by two sequential nucleophilic acyl substitution reactions, one that covalently binds an acyl group to the side chain -OH of a serine residue on the enzyme and a second that frees the fatty acid from the enzyme. 

Figure 29.2 MECHANISM Mechanism of action of lipase. The active site of the enzyme contains a catalytic triad of aspartic acid, histidine, and serine, which react cooperatively to carry out two nucleophilic acyl substitution reactions. Individual steps are explained in the text.

Design your own degradative pathway. You know the rules (organic mechanisms), and you ve seen the kinds of reactions that occur in the biological degradation of fats and carbohydrates inLo acetyl CoA. If you were Mother Nature, what series of steps would you use to degrade the amino acid serine into acetyl CoA ... 

Lipases have also been used as initiators for the polymerization of lactones such as /3-bu tyro lac tone, <5-valerolactone, e-caprolactone, and macrolides.341,352-357 In this case, the key step is the reaction of lactone with die serine residue at the catalytically active site to form an acyl-enzyme hydroxy-terminated activated intermediate. This intermediate then reacts with the terminal hydroxyl group of a n-mer chain to produce an (n + i)-mer.325,355,358,359 Enzymatic lactone polymerization follows a conventional Michaelis-Menten enzymatic kinetics353 and presents a controlled character, without termination and chain transfer,355 although more or less controlled factors, such as water content of the enzyme, may affect polymerization rate and the nature of endgroups.360... 

Although the tosylation reaction of fully protected serine has already been described,5 we have found that extended reaction times are required when the reaction is carried out on 100-200 mmol scale, taking from 3 to 5 days to go to completion. As a result of longer reaction times, the amount of byproducts is increased making the purification step more difficult. 

The first step, which is called the acylation reaction, involves a formation of an acyl-enzyme where the RC(0 )X group is covalently bound to the specially active serine residue and the XH group is expelled from the active site. The second step, which is called the deacylation step, involves an attack of an HY group on the acyl-enzyme. Here we concentrate on the acylation step which is the reverse of the second step when X and Y are identical. 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

Another consequence of application of organic solvents as a reaction medium is associated with the mechanism of enzyme-catalyzed transformations. According to the commonly accepted mechanism, the first product of the interaction of a hydrolytic (serine) enzyme with an ester is an O-acylenzyme (Scheme 5.4). When the reaction is performed in an aqueous solution, water acts as a nucleophile in the next step, to give acid B. If more nucleophilic hydrogen peroxide is present in the reaction mixture, peroxycarboxylic acids C are formed. However, in organic solvents the O-acylenzyme also reacts readily with other nucleophiles, such as... 

The antibiotic activity of certain (3-lactams depends largely on their interaction with two different groups of bacterial enzymes. (3-Lactams, like the penicillins and cephalosporins, inhibit the DD-peptidases/transpeptidases that are responsible for the final step of bacterial cell wall biosynthesis.63 Unfortunately, they are themselves destroyed by the [3-lactamases,64 which thereby provide much of the resistance to these antibiotics. Class A, C, and D [3-lactamases and DD-peptidases all have a conserved serine residue in the active site whose hydroxyl group is the primary nucleophile that attacks the substrate carbonyl. Catalysis in both cases involves a double-displacement reaction with the transient formation of an acyl-enzyme intermediate. The major distinction between [3-lactamases and their evolutionary parents the DD-peptidase residues is the lifetime of the acyl-enzyme it is short in (3-lactamases and long in the DD-peptidases.65-67... 

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