Flashcards in Clinical Correlates 3 Enzymes Deck (17):
The ___ ___ valacyclovir and valganciclovir are valine ester prodrugs of the antiviral acyclovir (treating herpes simplex virus types 1 and 2 and varicella-zoster infections) and ganciclovir (treating cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome [AIDS]), respectively. This new therapeutic approach involves a ‘‘prodrug’’ that is activated and converted by __ ___ enzymes to an active drug with higher bioavailability and efficacy. Famciclovir is another acyclovir compound used for shingles and recurrent outbreaks of herpes simplex virus type 2.
hepatic and intestinal
The optimal pH for pepsin is ?, reflecting its need as a digestive enzyme in the acidic gastric juice of the stomach. The optimal pH for alkaline phosphatase is
?, reflecting the basic pH environment in bone.
The drug ____, used in the treatment of tuberculosis, is acetylated by an N-acetyltransferase. A polymorphism of the enzyme exists, and individuals are classified into two groups: in the first group, the fast acetylators/metabolizers clear the drug from blood about ____faster than in the second group of individuals, the slow acetylators/poor metabolizers, in whom the presence of drug is prolonged, causing ___ ___. The Km (affinity of ___ substrate) is normal, but the Vmax of ‘‘fast’’ N-acetyltransferase, is three times normal.
hepatotoxicity and neuropathy
Hypersensitivity to alcohol exists when drinking small amounts of alcohol causes facial flushing and tachycardia (rapid heartbeat). Alcohol dehydrogenase generates ___, which is converted to acetate by ___. The latter enzyme exists in two forms, a high-affinity (low Km) form and a low-affinity (high Km) form. Those sensitive to alcohol lack the high-affinity form, resulting in excess acetaldehyde and, hence, ____.
Drugs such as ___, a competitive reversible inhibitor of ____, are used to treat a variety of diseases such as glaucoma (increased intraocular pressure) and myasthenia gravis (an autoimmune disease acting at the neuromuscular junction).
Angiotensin-converting enzyme (ACE) inhibitors, such as ________, are the most commonly used antihypertensive therapies that inhibit formation of angiotensin II, an octapeptide from angiotensin I.
captopril, enalapril, and lisinopril
A common noncompetitive inhibitor is a result of ___ (metal binding) therapy, such as ethylenediamine tetraacetic acid (EDTA), resulting in removal of required divalent metal ions from the active site of enzymes. Blood of patients is collected in tubes
with EDTA to inhibit both calcium-activated proteases and the blood coagulation pathway.
Nerve gases, agents of chemical terrorism such as tabun and sarin, and alkylphosphate insecticides (malathion) are ___ inhibitors of acetylcholinesterase. These compounds are also termed ‘‘suicide’’ inhibitors, creating a reactive group irreversibly reacting in the active site, forming an extremely stable intermediate.
___links the insulin A and B chains in proinsulin. The peptide is removed by proteolytic processing via carboxypeptidase E, yielding active insulin. Mutations in carboxypeptidase E rendering it inactive or lowering its activity may cause hyperproinsulinemia and diabetes in the homozygous state.
Hemostasis and thrombosis are mediated by enzymes along cascading steps of the blood coagulation pathways. Inherited deficiencies of clotting factors result
in uncontrolled bleeding. ____deficiency causes hemophilia A, an ___disease rife in some European royal families.
Isoenzymes (or isozymes) are enzymes composed of different amino acid sequences that catalyze the same reaction. Isozymes also differ in many of their physical properties.
Tissues contain characteristic isozymes or mixtures of isozymes. Enzymes such as creatine kinase (CK) differ from one tissue to another. Knowing which isozyme is elevated can be indicative of specific tissue damage.
Creatine kinase contains two subunits
Each subunit may be either of the muscle (M) or the
brain (B) type. Three isozymes exist (MM, MB, and BB). The MB fraction is most prevalent in heart muscle.
With regard to isozyme distribution, CK-MM makes up 99% of skeletal muscle and about 75% of myocardium. CK-MB makes up about 25% of myocardium, but it is not found in any other tissues, so ___ is a significant marker for a ____ (heart attack, MI). CK-MB levels begin to rise within a few hours of an MI and remain elevated for up to ___. This is used in conjunction with another protein marker, ___.
1. Allopurinol is used in the treatment of gout because of its ability to inhibit xanthine oxidase. This inhibition makes it impossible for the enzyme to degrade xanthine and hypoxanthine, which reduces the synthesis of urate, the culprit of gout. Allopurinol works through which one of the following mechanisms?
(A) Suicide inhibition
(B) Noncompetitive inhibition
(C) Allosteric interaction with the enzyme that
(D) Feedback inhibition
(E) Subunit cooperativity
A. Allopurinol is a substrate for xanthine oxidase, which converts allopurinol to oxypurinol, and which binds tightly to the enzyme and is not released from the enzyme. This blocks substrate binding and further activity of the enzyme. This is an example of irreversible suicide inhibition. Such inhibition leads to a decrease of Vmax. Noncompetitive inhibition occurs when inhibitors bind to a site other than the active site, which is not the case with allopurinol. Additionally, noncompetitive inhibitors are not substrates for the enzyme, as are suicide inhibitors. There is no end-product regulation of xanthine oxidase by allopurinol, thereby ruling out feedback inhibition. Cooperativity exists when there are two or more sites for substrate binding (and in positive cooperativity it is easier for substrate to bind as the concentration of substrate is increased), but this is not observed with xanthine oxidase.
2. A 10-year-old boy presents with vomiting, sweating, drooling, and a decreased heart rate. His friends state that he was in a corn field when it was sprayed by a crop duster. The chemical being sprayed was an organophosphate derivitive that covalently binds to acetylcholinesterase and inactivates the enzyme. What type of inhibition is being displayed?
C. This is an example of irreversible inhibition because a covalent bond has been formed between the inhibitor and the required serine at the active site of the enzyme. This enzyme can only be reactivated if that covalent bond is hydrolyzed, which is unlikely. Both competitive and noncompetitive binding are reversible because the inhibitor is not covalently linked to the enzyme. Allosteric inhibitors also bind to enzymes via noncovalent forces, and feedback inhibition refers to the normal regulation of a pathway by an end product of the pathway.
3. Nerve agents are toxic substances used in chemical warfare that add covalently to the enzyme acetylcholinesterase, thereby preventing the enzyme from hydrolyzing acetylcholine. This results in persistent acetylcholine in the synapse and continual muscle contractions. Which of the following substances can directly reactivate acetylcholinesterase after exposure to
such a toxin?
(A) Pralidoxime chloride
A. Pralidoxime chloride (2-PAM) is the nerve agent antidote that reactivates the poisoned acetylcholinesterase. Nerve agents (e.g., Sarin, VE) inhibit acetylcholinesterase by phosphorylation of the active site serine hydroxyl group of the enzyme. 2-PAM reactivates the cholinesterase by removing the phosphoryl group that is bound to the serine hydroxyl side chain and creates inactivated organophosphate and pralidoxime that undergo rapid metabolism and removal from the synapse. Atropine is a competitive antagonist for the muscarinic acetylcholine receptor and decreases the effects of acetylcholine. Although it is used in nerve agent poisoning, it does not directly reactivate the poisoned Acetylcholinesterase. Scopolamine is an anticholinergic competitive anatagonist at muscarinic (M1) acetylcholine receptors used to treat nausea and eye conditions that require mydriasis (e.g., iritis, uveitis). Scopolamine does not reactivate inhibited acetylcholinesterase. Ipratropium is a nonselective anticholinergic that blocks muscarinic receptors in the lung and decreases bronchoconstriction and mucus secretion, but has no direct effect on acetylcholinesterase. Diphenhydramine is an antihistamine, which has no effects on acetylcholinesterase.