Enzymes continued inhibition

Once kiside the host ceU, the vims must repHcate its own nucleic acid. To do this, it often uses part of the normal synthesizing machinery of the host ceU. If the vims is to continue its growth cycle, vkal nucleic acid and vkal proteki must be properly transported within the ceU, assembled kito the kifective vims particle, and ultimately released from the ceU. AH of these fundamental processes kivolve an intimate utilization of both ceUular and vkal enzymes. Certain enzymes that ate kivolved ki this process ate specificaHy suppHed by the invading vims. It is this type of specificity that can provide the best basis for antivkal chemotherapy Thus an effective antivkal agent should specificaHy inhibit the vkal-encoded or vims-kiduced enzymes without inhibition of the normal enzymes involved in the biochemical process of the host ceH. Vims-associated enzymes have been reviewed (2,3) (Table 1). 

The utilization of ammonia resulting from the combination of carbamyl phosphate with aspartic acid, the initial reaction for the synthesis of the pyrimidine nucleotides, continues only as long as there is a requirement for them (Fig. 3). Regulation of this biosynthetic pathway is probably by way of feedback inhibition of aspartate transcarbamylase. The rat liver enzyme is inhibited by uridine, cytidine or thymidine or such derivatives as CMP, UTP, or TMP, all intermediates or products of this pathway (B8). This is not the only enzyme of the pathway which may be subject to feedback regulation. Dihydroorotase from rat liver is also inhibited by some pyrimidines and purines (B9). 

Biocatalysts in nature tend to be optimized to perform best in aqueous environments, at neutral pH, temperatures below 40 °C, and at low osmotic pressure. These conditions are sometimes in conflict with the need of the chemist or process engineer to optimize a reaction with respect to space-time yield or high product concentration in order to facilitate downstream processing. Furthermore, enzymes and whole cells are often inhibited by products or substrates. This might be overcome by the use of continuously operated stirred tank reactors, fed-batch reactors, or reactors with in situ product removal [14, 15]. The addition of organic solvents to increase the solubility of substrates and/or products is a common practice [16]. 

Acetylsalicylic acid irreversibly inhibits both COX-1 and COX-2 by acetylating the enzymes. Since mature platelets lack a nucleus, they are unable to synthesise new enzyme. The anti-platelet effects of acetylsalicylic acid persist therefore throughout the lifetime of the platelet and the half-life of this effect is thus being much longer than the elimination half-life of acetylsalicylic acid (15 min). Since new platelets are continuously launched into the circulation, the clinically relevant anti-platelet effect of aspirin lasts for up to five days. This is the reason why low doses of acetylsalicylic acid (ca. 100 mg per day) are sufficient in the prophylaxis of heart attacks. 

Figure 10.1. Schematic diagram showing inhibition of synthesis of amino acids a) single chain inhibition occurs when enzyme controlling committed step (S ) is inhibited by increasing concentrations of product AAj b) branched chain inhibition of by increased concentration of AA2 occurs at a post-branching step (sj), while permitting continued production of product of other branch (AAj). In general, each step is controlled by a single enzyme.

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Keto con azole Inhibits several 200 mg twice reactions develops with continued use. Hematologic disturbances and hypothyroidism also seen. Generally well High potential for drug interactions due to potent induction of hepatic enzymes. Effective in a majority of causes ... 

Fluorouracil Inhibition of the enzyme thymidylate synthase, the rate-limiting step in thymidine formation. Dose-limiting Myelosuppression and mucositis with bolus administration Diarrhea and hand-foot syndrome with continuous infusion Additional toxicities Skin discoloration, nail changes, photosensitivity, and neurologic toxicity... 

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