Antimetabolites competitive

Antimetabolite. A compound that, by competitive blockade of the necessary enzymes, blocks metabolism. 

Donald Woods discovered that sulphonamides exerted their action by inhibiting an enzyme used by bacteria to synthesise folic acid. The compound 4-aminobenzoic acid is the precursor for folic acid, and is structurally similar to sulphonamide. Bacteria that were unable to synthesise folic acid were unable to achieve de novo synthesis of purines for their DNA and RNA synthesis and hence could not proliferate. Such competitive inhibitors, which mimicked normal metabolites, became known as antimetabolites (many are used in cancer chemotherapy. Chapter 21). 

Antimetabolites are enzyme inhibitors (see p. 96) that selectively block metabolic pathways. The majority of clinically important cytostatic drugs act on nucleotide biosynthesis. Many of these are modified nucleobases or nucleotides that competitively inhibit their target enzymes (see p. 96). Many are also incorporated into the DNA, thereby preventing replication. 

Thus sulfonamides are bacteriostatic drugs that inhibit bacterial growth by interfering with the microbial synthesis of folic acid. More specifically, sulfonamides block the biosynthetic pathway of folic acid synthesis, thus competitively inhibiting the transformation of p-aminobenzoic acid to folic acid (mediated by the enzyme dihydropteroate synthetase), which allows them to be considered as antimetabolites. 

Antimetabolite inhibitors of DNA synthesis act by the competitive or allosteric inhibition of a number of different enzymes participating in purine or pyrimidine biosynthesis. Actually, some such compounds interfere with as many as 10-12 different enzymes— although admittedly to a different degree. 

It was previously thought that 5-FU inhibits the enzyme by classical competitive inhibition. However, it was found that 5-FU is a transition-state substrate, and it forms a covalent complex with tetrahydrofolate and the enzyme in the same way that the natural substrate does. The reaction, however, will not go to completion, since the fluoro-uridine derived from the antimetabolite remains attached to the enzyme, and the latter becomes irreversibly deactivated. Recovery can occur only through the synthesis of new enzyme. Fluorouracil is used in the treatment of breast cancer and has found limited use in some intestinal carcinomas. Unfortunately, this drug has the side effects usually associated with antimetabolites. Its prodrug, fluorocytosine (8.35, which is also an antifungal agent) is better tolerated. 

The mode of action of sulfanilamides became known around 1947, when the structure and biosynthesis of folic acid were elucidated. This compound is built by bacteria from the heterocyclic pteroyl moiety, p-aminobenzoate, and glutamate. p-Aminobenzene-sulfonamide (9.89, sulfanilamide) is a competitive inhibitor of the synthase enzyme, acting as an antimetabolite of p-aminobenzoate. Occasionally, the sulfanilamide can even be incorporated into the modified folate, resulting in an inactive compound and thus an inactive enzyme. This theory, proposed by Woods and Fildes in 1940, became the first molecular explanation of drug action. 

Antimetabolites are analogues of normal DNA components or of coenzymes involved in nucleic acid synthesis. They get incorporated or competitively inhibit utilization of normal substrate to form dysfunctional nucleic acid molecules. 

Mammals must obtain their tetrahydrofolate requirements from their diet, but microorganisms are able to synthesize this material. This offers scope for selective action and led to the use of sulphanilamide and other antibacterial sulpha drugs, compounds which competitively inhibit dihydropteroate synthase, the biosynthetic enzyme incorporating p-aminobenzoic acid into the structure. These sulpha drugs thus act as antimetabolites of p-aminobenzoate. Specific dihydrofolate reductase inhibitors have also become especially useful as antibacterials,... 

Cytarabine (cytosine arabinoside, ara-C) is an S phase-specific antimetabolite that is converted by deoxycytidine kinase to the 5 -mononucleotide (AraCMP). AraCMP is further metabolized to the triphosphate (AraCTP), which competitively inhibits DNA polymerase and results in blockade of DNA synthesis. Cytarabine is also incorporated into RNA and DNA. Incorporation into DNA leads to interference with chain elongation and defective ligation of fragments of newly synthesized... 

The sulfonamides, or sulfa drugs, date back to the early 1900s but were not systematically studied until the 1930s. Sulfanilamide (A.17), a key reagent in the synthesis of certain dyes, was the first widely marketed sulfonamide (Figure A.5). Sulfonamides are antimetabolites and competitively inhibit a bacterial enzyme, dihydropteroate synthetase (DHPS) (see Chapter 1 and Chapter 6). DHPS plays a role in the synthesis of tetrahydrofolic acid (THF), an important compound in the preparation of thymidine. Because they limit the... 

Figure 1.12. Stractures of the sulfonamide drag prontosil rubrum , its antibacterially active metabolite sulfanilamide, and the bacterial metabolite p-Aminobenzoic acid. Sulfanilamide acts as an antimetabolite (i.e., competitive inhibitor) in the synthesis of folic acid, of which aminobenzoic acid is a component...

Antimetabolites are synthetic analogues of normal metabolites and act by competition, i.e. they deceive or defraud bodily processes. 

Faverin fluvoxamine. fazadinium bromide [ban. inn] is a bisquaternary amine complex heterocyclic compound, which acts as a NICOTINIC cholinoceptor ANTAGONIST, a (competitive) NEUROMUSCULAR BLOCKING AGENT. It can be used as a SKELETAL MUSCLE RELAXANT in anaesthesia, fazarabine [inn, usan] (Ara-Ac NSC 281272) is an analogue of cytarabine, an antimetabolite cytotoxic agent that has been used in ANTICANCER treatment. 

The inhibitory activity of an antimetabolite depends on its successful competition with the corresponding metabolite for the enzyme(s) of which the metabolite is the natural substrate or cofactor. Thus, the first requirement for the activity of any type of antimetabolite is, that it should be able to combine with the enzyme in such manner as to prevent effective complexing of the enzyme with... 

A. The antimetabolite plays the role of a substrate If the antimetabolite is capable of undergoing the enzyme-catalyzed reaction with the resulting dissociation of the enzyme-antimetabolite complex into (abnormal) produces) and the free enzyme, then it may be considered an abnormal substrate, or substitute metabolite. As such, it will competitively interfere with the transformation of the normal metabolite the extent of such interference depends on the relative affinity of the antimetabolite for the enzyme as well as on the rate of its conversion and subsequent release by the enzyme (i.e., the turn-over rate of the enzyme-antimetabolite complex). In the extreme (but important) case when the affinity is very high and the turnover rate very low, such antimetabolites act, in effect, as potent enzyme inhibitors, rather than as substitute metabolites (see B.iii) below). In the majority of cases, those classical antimetabolites which are capable of undergoing the enzyme-catalyzed reaction, having affinities and conversion rates comparable to those of the corresponding normal metabolites, exert only a partial and temporary inhibition at those steps of the metabolic pathway in which they themselves are metabolized, and therefore, their effective action as metabolic inhibitors will depend on their inhibition of other targets and on subsequent metabolic events (see Section 2.3.). 

However, this does not apply to the special situation when (1) the enzyme is a synthetase which catalyzes the formation of a covalent bond between the metabolite (or antimetabolite) and a second substrate, and (2) the second substrate is available only in a limited amount. In this case, the antimetabolite competes with the metabolite not only for the enzyme but also for the second substrate, with which it will combine covalently to form an inert product. Although this enzyme-mediated reaction of the antimetabolite is reversible by the corresponding metabolite in a competitive manner, due to its potentially crucial metabolic effect, (i.e., the elimination of another, limiting metabolite which is required for the same reaction step of the metabolic pathway), this reaction per se could be responsible for the over-all inhibitory effect of the antimetabolite. That is, in such particular cases, the metabolic target of the inhibitory action of the antimetabolite may be an enzymic reaction step in which it actually plays the role of a substrate. One might think that this type of situation is a rather special and unusual one, as it may be indeed however, it so happens that the first descovered and still important class of classical and semi-classical antimetabolites, the sulfonamides, appears to act in this manner, as indicated by the results of a recent study8 (see Section 3.2.). 

A. Metabolic activation The antimetabolites (and their subsequent enzymic reaction product(s), respectively) may be utilized as competitive substrate(s) in one (or several consecutive) enzymic reaction(s) along the metabolic pathway of the normal metabolite, but at one stage of the metabolic reaction sequence, the transformed analogue cannot be further utilized as a substrate and, instead, acts as an inhibitor of the enzyme which catalyzes the next reaction step. At this stage, the action of the transformed ( activated ) analogue as an enzyme inhibitor depends on the same general types of structural requirements as outlined in the case of the directly acting enzyme inhibitors (see Section 2.2. ... 

Replacement of H with CH3 frequently confers antimetabolite activity. Some of the more interesting examples are the methyltryptophans (56-58) (substituted in the 5- or 6-positions of the ring, or in the /3-position of the alanine side chain) which inhibit competitively the pancreatic tryptophanactivating enzyme13 in addition 5-methyltryptophan acts as both feedback inhibitor and repressor of the endogenous synthesis of tryptophan45. Ethio-... 

The antimetabolites discussed so far, are all compounds of relatively small molecular weight. In the majority of cases, they act by competitively inhibiting the metabolic transformations of the analogous normal metabolites which usually are intermediates (precursors) or cofactors in the biosyntheses of nucleic acids and proteins. In some other cases, the inhibitory action of the antimetabolites is a consequence of their incorporation into the macromolecules (see Section 2.3. B) however, also this type of action depends on their... 

Methotrexate, a common antimetabolite, was introduced several decades ago for the treatment of psoriasis and remains an effective therapeutic approach. It is a synthetic analogue of folic acid that acts as a competitive inhibitor of the enzyme dihydrofolate reductase, that is responsible for the conversion of dihydrofolate to tetrahydrofolate. Tetrahydrofolate is an essential cofactor for the synthesis of thymidy-late and purine nucleotides required for DNA and RNA synthesis. Methotrexate inhibits replication and function of T and B cells and suppresses secretion of various cytokines such as IL-1, IFN-y,... 

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