Which of the following statements is not true of competitive inhibitors ?
A) Vmax remains the same
B) Apparent Km in increased
C) Inhibitor is a structural analogue of the substrate
D) Inhibitor binds covalently to the enzyme
E) Increasing concentration of substrate can reverse the changes
Figure- Difficulty in opening the eyelids in myashenia gravis
The answer is D-Inhibitor binds covalently to the enzyme.
Myasthenia gravis (MG)
Myasthenia gravis (MG) is a relatively rare autoimmune disorder of peripheral nerves in which antibodies form against acetylcholine (ACh) nicotinic postsynaptic receptors at the neuromuscular junction (NMJ).
The basic pathology is a reduction in the number of ACh receptors (AChR) at the postsynaptic muscle membrane brought about by an acquired autoimmune reaction producing anti-AChR antibodies.
MG is classified into 2 major clinical forms: ocular MG and generalized MG.
The reduction in the number of AChRs results in a characteristic pattern of progressively reduced muscle strength with repeated use and recovery of muscle strength after a period of rest. The bulbar muscles are affected most commonly and most severely, but most patients also develop some degree of fluctuating generalized weakness.
MG is one of the most treatable neurologic disorders. Pharmacologic therapy includes anticholinesterase medication and immunosuppressive agents. Anticholinesterase agents include pyridostigmine, neostigmine, and edrophonium while immunosuppressive agents include corticosteroids, Azathioprine, Cyclosporine A etc.
In the given case physostigmine is anticholinesterase medication that is known to act by competitive inhibition of Acetylcholinesterase. Acetylcholine is left undegraded.
In competitive inhibition, an enzyme can bind substrate (forming an ES complex) or inhibitor (EI) but not both (ESI). The competitive inhibitor resembles the substrate and binds to the active site of the enzyme (Figure-1). The substrate is thereby prevented from binding to the same active site.
A competitive inhibitor diminishes the rate of catalysis by reducing the proportion of enzyme molecules bound to a substrate. The hallmark of competitive inhibition is that it can be overcome by a sufficiently high concentration of substrate. Under these conditions, the substrate “outcompetes” the inhibitor for the active site. However, the apparent value of Km is altered; the effect of a competitive inhibitor is to increase the apparent value of Km. As the value of [I] increases, the value of Km increases (see Figure-2). In the presence of a competitive inhibitor, an enzyme will have the same Vmax as in the absence of an inhibitor. The inhibitor does not bind covalently to the enzyme to bring about irreversible changes. Thus in the given problem, all statements are true of competitive inhibitors except (D).
Figure-1-The competitive inhibitor resembles the substrate and binds to the active site of the enzyme. The substrate is thereby prevented from binding to the same active site.
Figure-2- As the concentration of a competitive inhibitor increases, higher concentrations of substrate are required to attain a particular reaction velocity. A sufficiently high concentrations of substrate can completely relieve competitive inhibition.
A brief summary of enzyme inhibitors is as follows-
|Type of Inhibition||Effect on Maximum Reaction Velocity (Vmax) and Km||Reversible/ Irreversible||Examples|
1) Inhibitor- a structural analogue
2) There is a competition between substrate and the inhibitor for the active site
|1) Vmax -Unchanged
2) Km -Increased
|Reversible||1) HMG Co A Reductase- inhibited by Statins-used as cholesterol lowering drugs.
2) Epoxide Reductase –inhibited by Dicumarol-used as an anticoagulant.
3) Dihydrofolate Reductase-inhibited by Methotrexate- used as anticancer drug.
4) Pteroyl Synthase-inhibited by PABA (Para- amino –benzoic –acid)-used as antibiotic.
5) Angiotensin converting enzyme Inhibitor- inhibited by Captopril –used as an antihypertensive drug.
6) Succinate dehydrogenase- inhibited by Malonate-acts as a poison.
7) Lactate dehydrogenase-inhibited by Oxamate- acts as a poison.
|Noncompetitive 1) Inhibitor binds at a site other than the active site.
2) Not a structural analogue
|Can be reversible or irreversible||1) Enolase is inhibited by Fluoride used for sample collection for glucose estimation.
2) PDH complex, Alpha ketoglutarate dehydrogenase complex, glyceraldehyde-3-P dehydrogenase
(-SH group containing enzymes) are inhibited by Arsenate, acts as a slow poison
3) Cytochrome oxidase- Inhibited by
cyanide, which acts as a poison.
|Suicidal inhibition, also called Mechanism based inhibition
Inhibitor gets activated by host enzyme to inhibit the subsequent enzyme
2) Km- Increased
|Irreversible||1)Inhibition of Xanthine oxidase by Allopurinol, used for the treatment of gout.
2) Inhibition of Aconitase by fluoroacetate-used as a rat poison
3) Inhibition of Thymidylate synthase by 5-FU (5-Fluorouracil)used as an anticancer drug
4) Inhibition of Ornithine decarboxylase by-Di Fluoro methyl ornithine(DFMO)
5) Mono Amine Oxidase is inhibited by Deprenyl used to treat Parkinson disease and depression.
|Allosteric Inhibition (Binding of the inhibitor alters either the affinity of the enzyme for its substrate or the reaction velocity is decreased||1) Vmax is decreased in V type enzymes
2) Km is increased in K type enzymes
|Reversible||Most of them are physiological inhibitors.
1)ATP and Citrate are allosteric inhibitors of PFK-1
2) Fr 2,6 bisphosphate is an allosteric inhibitor of Fr1,6 bisphosphatase enzyme.
|Feed back inhibition, also called Product inhibition –
The product of the reaction pathway inhibits the key regulatory enzyme.
2) Km- constant
|Reversible depending upon the need of the product||1) Inhibition of HMG Co A Reductase by Mevalonate(Immediate product) and cholesterol(Final product)
2) Inhibition of Aspartate transcarbamoylase by
UTP and CTP, the products of this pathway.
|Un- competitive inhibition Inhibitor binds to the enzyme substrate complex||Vmax and Km -both are decreased||Irreversible||Inhibition of placental alkaline phosphatase- by Phenylalanine|
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