Biosynthesis enzymes inhibition

The significance of these in vitro enzyme inhibition studies is uncertain, in view of the evidence that has been presented concerning the sensitivity of cancer cells to feedback inhibition by these nucleotides. On the other hand, 6-chloropurine inhibits the de novo biosynthesis of nucleic acid guanine but not of nucleic acid adenine in sarcoma 180 ascites cells [319],... 

As a result, the penicillin occupies the active site of the enzyme, and becomes bound via the active-site serine residue. This binding causes irreversible enzyme inhibition, and stops cell-wall biosynthesis. Growing cells are killed due to rupture of the cell membrane and loss of cellular contents. The binding reaction between penicillinbinding proteins and penicillins is chemically analogous to the action of P-lactamases (see Boxes 7.20 and 13.5) however, in the latter case, penicilloic acid is subsequently released from the P-lactamase, and the enzyme can continue to function. Inhibitors of acetylcholinesterase (see Box 7.26) also bind irreversibly to the enzyme through a serine hydroxyl. 

Mechanism of Action An antihyperlipidemicthat interferes with cholesterol biosynthesis by inhibiting the conversion of the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) to mevalonate, a precursor to cholesterol. Therapeutic Effect Decreases LDL cholesterol, VLDL, and plasma triglyceride levels, increases HDL concentration. Pharmacokinetics Protein binding 88%. Minimal hepatic metabolism. Primarily eliminated in the feces. Half-life 19 hr (increased in patients with severe renal dysfunction). 

Ergosterol biosynthesis inhibitors via 14a-demethylase enzyme inhibition... 

GABA synthesis inhibitors act on the enzymes involved in the decarboxylation and transamination of GABA. Glutamic acid decarboxylase (GAD), the first enzyme in GABA biosynthesis, is inhibited easily by carbonyl reagents such as hydrazines [e.g., hydrazinopropionic acid (4.164) or isonicotinic acid hydrazide (4.165)], which trap pyridoxal, the essential cofactor of the enzyme. A more specific inhibitor is allylglycine (4.166). All of these compounds cause seizures and convulsions because they decrease the concentration of GABA. 

Morpholines such as tridemorph (9.112) attack sterol biosynthesis via A -reductase enzyme inhibition and are valuable agricultural fungicides. 

It inhibits the terminal steps in uric acid biosynthesis by inhibiting enzyme xanthine oxidase. During therapy with allopu-rinol the uric acid plasma levels decline. 

Acivicin is a potent inhibitor of several steps in purine nucleotide biosynthesis that utilize glutamine. The enzymes it inhibits are glutamine PRPP amidotransferase (step 1, fig. 23.10), phosphoribosyl-A-formylglycinamidine synthase (step 4, fig. 23.10), and GMP synthase (see fig. 23.11). In pyrimidine nucleotide biosynthesis the enzymes inhibited are carbamoyl synthase (step 1, fig. 23.13) and CTP synthase (see fig. 23.14). Acivicin is under trial for the treatment of some forms of cancer. 

Many lines of evidence indicate that the first committed step in de novo purine nucleotide biosynthesis, production of 5-phosphoribosylamine by glutamine PRPP amidotransfer-ase, is rate-limiting for the entire sequence. Consequently, regulation of this enzyme is probably the most important factor in control of purine synthesis de novo (fig. 23.24). The enzyme is inhibited by purine-5 -nucleotides, but the most inhibitory nucleotides vary with the source of the enzyme. Inhibition constants (A, ) are usually in the range 10-3-10-5 M. The maximum effect of this end-product inhibition is produced by certain combinations of nucleotides (e.g., AMP and GMP) in optimum concentrations and ratios, indicating two kinds of inhibitor binding sites. This is an example of a concerted feedback inhibition. 

All biosynthetic pathways are under regulatory control by key allosteric enzymes that are influenced by the end products of the pathways. For example, the first step in the pathway for purine biosynthesis is inhibited in a concerted fashion by nucleotides of either adenine or guanine. In addition, the nucleoside monophosphate of each of these bases inhibits its own formation from inosine monophosphate (IMP). On the other hand, adenine nucleotides stimulate the conversion of IMP into GMP, and GTP is needed for AMP formation. 

Kreuzman AJ, Turner JR, Yeh WK (1988) Two distinctive O-methyltransferases catalyzing penultimate and terminal reactions of macrolide antibiotic (tylosin) biosynthesis. Substrate specificity, enzyme inhibition, and kinetic mechanism. J Biol Chem 263 15626-15633... 

Even though AMP, not cAMP, may be the protein kinase activator, glucagon causes its activation and insulin, inactivation. Details on such hormone effects are lacking. Also recall that malonyl-CoA inhibits palmitoyl-CoA-camitine acyltrans ferase, the rate-controlling enzyme in the /3-oxidation process. Thus, lipid oxidation is inhibited in an environment that favors lipid synthesis, as in the fed state, whereas lipid biosynthesis is inhibited in an environment favoring lipid oxidation, as in fasting. 

Scott DE, Ciulli, Abell C. Coenzyme biosynthesis enzyme mechanism, strucmre and inhibition. Nat. Prod. Rep. 2007 24 1009-1026. 50. 

The cephalosporins and penicillins are thought to have a similar, if not identical, mode of action. The antibiotics interfere with cell wall biosynthesis by inhibiting enzymes concerned with the structural integrity of the cell wall [90]. 

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