Enzyme and their inhibitors

Objective:

This page enlists some enzyme and enzyme systems with which important drugs interact and exert their pharmacological actions.

Disclaimer

Most of the content in this page are collected from Google and Google AI Overview. These are for informational purposes only. For medical advice or diagnosis, consult a professional. AI responses may include mistakes. 

Acetylcholinesterase – Acetylcholinesterase (AChE) is an enzyme that breaks down the neurotransmitter acetylcholine (ACh), primarily at nerve and muscle junctions, to terminate signaling and prevent overstimulation. It hydrolyzes acetylcholine into acetic acid and choline, which is then recycled to make new acetylcholine. Because it is vital for nervous system function, substances that inhibit AChE can be both toxic (like some pesticides and nerve agents) and therapeutic (like some drugs for myasthenia gravis or Alzheimer's).

Drugs that inhibit acetylcholinesterase include medications for Alzheimer's disease like donepezil, galantamine, and rivastigmine, as well as drugs used for myasthenia gravis such as pyridostigmine and neostigmine. Other examples include physostigmine and, in the context of chemical weapons, the organophosphates sarin and chlorpyrifos.

For Alzheimer's disease, remember "I Don'Tactually remember mine in riverside gala-night" for Donepesil, Tacrine, rivastigmine and galantamine. 

Angiotensin-converting enzyme (ACE) – Angiotensin-converting enzyme (ACE) is an enzyme crucial for regulating blood pressure by converting angiotensin I to the potent vasoconstrictor angiotensin II. Angiotensin II causes blood vessels to narrow, raising blood pressure. ACE inhibitors are a class of drugs that block the action of ACE, leading to relaxed blood vessels, lower blood pressure, and reduced strain on the heart and kidneys.  

Drugs that inhibit the Angiotensin-converting enzyme (ACE) include benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. These medications, often called ACE inhibitors, are commonly used to treat high blood pressure and heart failure. To remember, memorise Angiotensin-convers APRIL.

Aromatase – Aromatase is an enzyme that converts androgens (like testosterone) into estrogens, playing a key role in estrogen production throughout the body. It is encoded by the CYP19A1 gene and is found in various tissues, including the brain, bone, and adipose tissue. Because aromatase's activity is crucial for estrogen-dependent conditions like certain breast cancers, inhibiting it with aromatase inhibitors is a major treatment strategy

Drugs that inhibit aromatase include anastrozole , letrozole, and exemestane. These medications are commonly used to treat certain types of breast cancer in postmenopausal women by reducing the amount of estrogen in the body. 

Beta-lactamase – Beta-lactamase is an enzyme produced by bacteria to break the beta-lactam ring of beta-lactam antibiotics, such as penicillins and cephalosporins, rendering them ineffective. This enzyme is a major cause of antibiotic resistance and can be encoded on chromosomes or mobile genetic elements like plasmids. It is used by bacteria to inactivate antibiotics before they can kill the cell, and understanding beta-lactamase types is crucial for clinical decision-making.

Drugs that inhibit Beta-lactamase include commonly used inhibitors like clavulanic acid, sulbactam, and tazobactam, which are often combined with beta-lactam antibiotics to increase their effectiveness. Newer inhibitors, such as avibactam, relebactam, and vaborbactam, have also been developed to combat a wider range of these enzyme

Carbonic anhydrase – Drugs that inhibit carbonic anhydrase include acetazolamide, methazolamide, dorzolamide, brinzolamide, and dichlorphenamide, which are used for conditions like glaucoma, edema, and epilepsy. Topiramate also acts as a carbonic anhydrase inhibitor.

Other drugs that interact with carbonic anhydrase include many classes, most notably nonsteroidal anti-inflammatory drugs (NSAIDs) and anticonvulsants, which can cause toxicity or alter efficacy. Other interacting drugs include lithium, oral contraceptives, antifungals, metformin, and corticosteroids, with interactions often leading to adverse effects like salicylate toxicity, hyperkalemia, or low blood sugar. Some drug combinations, like certain anticancer drugs or specific antiepileptics, are being investigated for synergistic effects.

Cyclooxygenase (COX) – 

Drugs that inhibit cyclooxygenase (COX) include non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, naproxen, and aspirin, as well as selective COX-2 inhibitors like celecoxib. These drugs block the COX enzymes, which are responsible for producing prostaglandins, thereby reducing pain, inflammation, and fever.

Dihydrofolate reductase – Dihydrofolate reductase (DHFR) is an enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate, a crucial step in the synthesis of purines, thymidylate, and certain amino acids. It is a key target for various drugs, including antifolates, which are used to treat cancer, certain inflammatory diseases like rheumatoid arthritis, and infectious diseases. In humans, DHFR is encoded by the DHFR gene, located on chromosome 5. 

Drugs that inhibit dihydrofolate reductase (DHFR) include methotrexate, trimethoprim, and pyrimethamine. Methotrexate is used as an anticancer and anti-inflammatory drug, while trimethoprim is used to treat bacterial infections and pyrimethamine is used to treat protozoal infections. Another example is cycloguanil, an antimalarial drug which is a prodrug that is metabolized into its active form.

DNA gyrase – DNA gyrase is a bacterial enzyme that relieves topological strain in DNA by introducing negative supercoils, a process crucial for DNA replication and transcription. It is a type II topoisomerase that works by cutting both strands of DNA, passing another segment through the break, and then resealing it, which is an ATP-dependent process. Because it is essential in bacteria, DNA gyrase is a valuable target for antibiotics, particularly the fluoroquinolone class, which inhibits its function. 

Drugs that inhibit DNA gyrase include fluoroquinolones (like ciprofloxacin, levofloxacin, and moxifloxacin), aminocoumarins, and cyclothialidines. Other inhibitors are proteinaceous toxins such as CcdB and microcin B17, and synthetic compounds like emodin analogues. These drugs work by either interfering with the enzyme's ability to rejoin double-strand breaks in DNA or by blocking its ATPase activity. 

DNA Polymerase – DNA RNA polymerase inhibitors work by binding to the active sites or other crucial regions of the polymerase enzymes, thereby preventing them from carrying out their functions. These inhibitors can be divided into several categories based on their mechanisms of action. Some inhibitors, like nucleotide analogs, resemble the natural substrates of DNA or RNA polymerases. When incorporated into the growing DNA or RNA chain, they cause premature termination of the chain elongation. Classic examples include the antiviral drug acyclovir, which targets viral DNA polymerase, and the cancer drug cytarabine, which inhibits human DNA polymerase.

DNA polymerase and DNA gyrase are different enzymes with distinct functions, DNA polymerase builds new DNA strands, while DNA gyrase relieves torsional strain by altering DNA supercoiling.

Dopa decarboxylase (DDC) – Dopa decarboxylase (DDC) is an enzyme that synthesizes neurotransmitters like dopamine from L-DOPA and serotonin from L-5-hydroxytryptophan. Also known as aromatic L-amino acid decarboxylase (AADC), this enzyme plays a critical role in the nervous system and is targeted by medications used to treat diseases like Parkinson's. 

Drugs that inhibit dopa decarboxylase include carbidopa and benserazide, which are commonly used with levodopa for Parkinson's disease. Other potential inhibitors, though not used for treatment, include natural compounds like epigallocatechin gallate (EGCG) found in green tea.

HMG-CoA reductase – HMG-CoA reductase is an enzyme that catalyzes the rate-limiting step in cholesterol synthesis by converting HMG-CoA to mevalonate. It is a crucial target for cholesterol-lowering drugs called statins, which inhibit its activity to reduce cholesterol levels in the blood. The enzyme's activity is tightly regulated by the cell to maintain lipid homeostasis, with feedback mechanisms that respond to cholesterol levels.

Drugs that inhibit HMG-CoA reductase are known as statins, which are a class of medications used to lower cholesterol. The approved statins include atorvastatin, rosuvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, and pitavastatin.

 Monoamine oxidase (MAO)  – Monoamine oxidase (MAO) is a family of enzymes that break down neurotransmitters like serotonin, dopamine, and norepinephrine, as well as dietary amines like tyramine. There are two types, MAO-A and MAO-B, which are found in different parts of the body and have varying substrate preferences. MAOIs, or monoamine oxidase inhibitors, are a class of drugs that block the action of these enzymes, which increases the levels of these neurotransmitters and is used to treat conditions like depression and Parkinson's disease.  

Drugs that inhibit monoamine oxidase (MAO) include irreversible MAOIs like phenelzine, tranylcypromine, isocarboxazid, and selegiline, which are used to treat depression and Parkinson's disease. Some reversible MAOIs, like moclobemide (available outside the US) and the antibiotic linezolid, are also available. To remember  irreversible monoamine oxidase (MAO) inhibitors (MAOIs), remember MAO SE TUNG is playing (MAOI, selegiline, tranylcypromine, isocarboxazid, respectively); Metallophone with Lina (moclobemide and linezolid, respectively, these two are reversible).

Sodium-potassium ATPase – Sodium-potassium ATPase (Na+/K+-ATPase), also known as the sodium-potassium pump, is an enzyme that actively transports three sodium ions (3Na+) out of a cell and two potassium ions (2K+) into the cell for every ATP molecule it consumes. This process establishes and maintains the electrochemical gradients for sodium and potassium ions across the cell membrane, which is essential for cell volume regulation, nerve impulse transmission, heart muscle contraction, and secondary active transport.  

Drugs that inhibit the sodium-potassium ATPase include cardiac glycosides like digoxin and digitoxin, certain calcium channel blockers, and other compounds such as promethazine, verapamil, propranolol, and FK506. These inhibitors have various medical applications, most notably in treating heart conditions.

Phosphodiesterase (PDE) – Phosphodiesterase (PDE) is a family of enzymes that regulates the levels of second messenger molecules, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), inside cells. By breaking down these molecules, PDEs control a wide range of cellular processes, including cell proliferation, inflammation, and metabolic functions. Pharmaceuticals that block PDE activity, known as PDE inhibitors, are used to treat various conditions such as erectile dysfunction, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD).

Drugs that inhibit phosphodiesterase (PDE) include a wide range of medications, categorized by the specific PDE they inhibit. Examples include PDE3 inhibitors like cilostazol and milrinone, PDE4 inhibitors such as roflumilast and apremilast, and PDE5 inhibitors like sildenafil and tadalafil. Non-specific inhibitors, such as theophylline, also exist.

Protease – A protease enzyme is a type of enzyme that breaks down proteins into smaller peptides or amino acids by hydrolyzing peptide bonds. They are found in all living organisms, including humans, animals, plants, fungi, and bacteria. Proteases are crucial for many biological processes like digestion, protein recycling, and blood clotting.  

Drugs that inhibit proteases include HIV protease inhibitors like ritonavir, atazanavir, and darunavir (names ending with "navir") as well as other drugs like apixaban (for blood clots), aprotinin (a serine protease inhibitor), and ivermectin (an antiviral and antiparasitic). These drugs work by blocking the activity of protease enzymes, which are crucial for the life cycle of viruses and other pathogens

RNA polymerase – RNA polymerase is a crucial enzyme that synthesizes RNA from a DNA template in a process called transcription. It is essential for gene expression in all living organisms, reading a DNA template to produce a single-stranded RNA copy. The enzyme's function is fundamental to life, allowing cells to respond to changes and perform necessary functions.

RNA polymerase inhibitors work by binding to the RNA polymerase enzymes and causing conformational changes that render them inactive. These inhibitors do not necessarily resemble the natural substrates but interfere with the enzyme's activity by distorting its structural integrity. Rifampicin, an antibiotic used to treat tuberculosis, is an example of this type of inhibitor, as it binds to bacterial RNA polymerase and prevents RNA synthesis.

Thrombin – Thrombin, also known as factor IIa, is an enzyme that plays a central role in blood clotting by converting fibrinogen into fibrin, which forms a mesh to stop bleeding. It is a serine protease produced from its precursor, prothrombin, and has multifaceted roles, including activating platelets and other coagulation factors, and promoting inflammation and cellular proliferation. 

Drugs that inhibit thrombin include direct thrombin inhibitors like bivalirudin, argatroban, and dabigatran, as well as indirect inhibitors like heparin, which works by enhancing antithrombin's inhibitory effect. Other drugs, such as the vitamin K antagonist warfarin, prevent thrombin formation.

Tyrosine kinase – A tyrosine kinase is an enzyme that acts as a cellular switch, transferring a phosphate group from ATP to a tyrosine residue on a protein, which can turn on or off various cellular functions like cell growth, division, and survival. Because they are crucial for cell signaling, malfunctions or overactivity of tyrosine kinases can contribute to diseases like cancer. Drugs called tyrosine kinase inhibitors (TKIs) can be used to block these malfunctioning enzymes and treat certain cancers.

How they work

Phosphorylation: Tyrosine kinases are enzymes that specifically "phosphorylate" a tyrosine amino acid in a protein. 

Signal transmission: This phosphorylation event changes the structure of the protein, allowing it to transmit signals within the cell. 

Cellular functions: This process regulates important cellular functions, including cell growth, migration, differentiation, and metabolism. 

Many drugs inhibit tyrosine kinases, including several used in cancer treatment like imatinib, sunitinib, gefitinib, erlotinib, and dasatinib. These drugs work by blocking specific tyrosine kinases, such as BCR-ABL, EGFR, and VEGFR, which are crucial for cell growth and are often overactive in cancer. Examples of specific drug-target pairings include imatinib (BCR-ABL, Kit, PDGFR) and alectinib (anaplastic lymphoma kinase or ALK). Suramin is also a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase.

Mnemonic to remember tyrosine kinases inhibitor used in cancer treatment is Imandar Sunnis Get Elongate ParaDISE (imatinib, sunitinib, gefitinib, erlotinib, and dasatinib respectively). Further reading: Hormones using Non-receptor tyrosine kinases (nRTKs). DNA RNA polymerase inhibitors, RNA Polymerase Inhibitorscy.

Xanthine oxidase – Xanthine oxidase is an enzyme that catalyzes the final steps in the breakdown of purines, converting hypoxanthine to xanthine and then to uric acid. It also produces superoxide anions (O2-), which are converted to other reactive oxygen species. High levels of uric acid can lead to conditions like gout, and drugs that inhibit xanthine oxidase, such as allopurinol, are used to treat it.

Drugs that inhibit xanthine oxidase include allopurinol, oxypurinol, and febuxostat. These are used to lower uric acid levels for conditions like gout. Topiroxostat is another xanthine oxidase inhibitor.

১৮️. Beta-lactamase – ক্ল্যাভিউলানিক অ্যাসিড

১৯️. 5-alpha reductase – ফিনাস্টারাইড

২০️. Aldose reductase – এপালরেস্টাট

২১️. Glutathione reductase – অ্যান্টিঅক্সিডেন্ট 

২২️. Topoisomerase II – ইটোপোসাইড

২৩️. H⁺/K⁺ ATPase (Proton Pump) – ওমিপ্রাজল, প্যান্টোপ্রাজল