Dihydrofolate reductase catalyzes the reduction of dihy- drofolate with NADPH as the reducing substrate. This enzyme is of special interest because several of its inhibitors have been used in the treatment of neoplastic disease, malaria, bacterial infections, psoriasis, and other disorders (1).
What is the function of dihydrofolate reductase?
Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF). THF is needed for the action of folate-dependent enzymes and is thus essential for DNA synthesis and methylation.
What is the function of reductase?
Reductase enzymes belong to the E.C. 1 class of oxidoreductases and catalyze reduction reactions. A reduction reaction involves the gain of electrons, it is usually coupled to oxidation and termed a redox reaction. Reductases lower the activation energy needed for redox reactions to occur.
What type of enzyme is dihydrofolate reductase?
Dihydrofolate reductase is an enzyme that converts dihydrofolate to tetrahydrofolate and is involved in purines and thymidylate synthesis. It is encoded by the human DHFR gene. Antifolate drugs, methotrexate (MTX) and trimetrexate, can tightly bind to DHFR and inhibit DNA synthesis and cell proliferation.
Where is dihydrofolate reductase found?
In humans, the DHFR enzyme is encoded by the DHFR gene. It is found in the q11→q22 region of chromosome 5. Bacterial species possess distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar.
Which reaction directly produces dihydrofolate?
DHFR catalyzes the two-step reduction of folic acid, first to dihydrofolate and then to the active coenzyme THF (Fig. 39.1). The enzyme is also responsible for the conversion of dihydrofolate, which is produced in the reaction of thymidine monophosphate biosynthesis, to THF (Fig. 39.1).
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How does trimethoprim inhibit dihydrofolate reductase?
Mechanism of Action
Trimethoprim is 50,000 to 100,000 times more active against bacterial dihydrofolate reductase than against the human enzyme. Trimethoprim interferes with the conversion of dihydrofolate to tetrahydrofolate, the precursor of folinic acid and ultimately of purine and DNA synthesis (Fig. 33-3).
What does HMG-CoA reductase do?
The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the conversion of HMG-CoA to mevalonate, a four-electron oxidoreduction that is the rate-limiting step in the synthesis of cholesterol and other isoprenoids.
What reductase means?
A reductase is an enzyme that catalyzes a reduction reaction.
What is the meaning of HMG-CoA reductase inhibitors?
Listen to pronunciation. (HMG-koh-A ree-DUK-tays in-HIH-bih-ter) A substance that blocks an enzyme needed by the body to make cholesterol and lowers the amount of cholesterol in the blood. HMG-CoA reductase inhibitor drugs are called statins.
What drugs inhibit dihydrofolate reductase?
Pyrimethamine and trimethoprim are the most widely used dihydrofolate reductase inhibitors. Pyrimethamine is a known terattogen but is more effective then trimethoprim, which is usually administered in conjunction with a dihydropteroate synthase inhibitor (sulfamethoxazole).
Which of the following is considered selective inhibitor of bacterial dihydrofolate reductase?
The diaminopyrimidine class of antibacterials, such as TMP (4), were developed over 40 years ago and brodimoprim (9), launched in 1993, is a selective inhibitor for bacterial DHFRs that has been widely used due to its broad-spectrum biological activity [35–37].
Is folic acid a substrate for dihydrofolate reductase?
Folic Acid as Substrate for DHFR.
Due to the slow rate of DHFR with FA, activity with this substrate was measured only by the HPLC method.
Is methotrexate a dihydrofolate reductase inhibitor?
Methotrexate is a dihydrofolate reductase inhibitor that is used in the treatment of autoimmune inflammatory diseases such as RA. Methotrexate inhibits inflammation even in low-dose treatment. Inflammatory markers as IL-6, CRP, and TNF-α are reduced in patients treated with methotrexate.
What enzyme is responsible for the activation of folate to its active form?
In the cells, folic acid is reduced to THF, a biologically active form, in a two-step process that requires two molecules of NADPH and the enzyme dihydrofolate reductase (DHFR).
What is the mechanism of action of methotrexate?
Methotrexate’s mechanism of action is due to its inhibition of enzymes responsible for nucleotide synthesis including dihydrofolate reductase, thymidylate synthase, aminoimidazole caboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyltransferase.
Is leucovorin folic acid?
Leucovorin is in a class of medications called folic acid analogs. It works by protecting healthy cells from the effects of methotrexate or similar medications while allowing methotrexate to enter and kill cancer cells.
What is folate metabolism?
Folate metabolism regulates changing of amino acids (homocysteine and methionine), purine and pyrimidine synthesis and DNA methylation. These whole biochemical processes have significant influence on hematopoietic, cardiovascular and nervous system functions.
Which enzyme is also known as folic acid?
Hence folic acid must first be reduced to THF. This four electron reduction proceeds in two chemical steps both catalyzed by the same enzyme, dihydrofolate reductase. Folic acid is first reduced to dihydrofolate and then to tetrahydrofolate.
Why does sulfonamide acts as a competitive inhibitor of DHPS?
In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthase, DHPS. DHPS catalyses the conversion of PABA (para-aminobenzoate) to dihydropteroate, a key step in folate synthesis.
What enzyme does sulfamethoxazole inhibit?
Mechanism of Action
Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase.
What are folate reductase inhibitors?
A dihydrofolate reductase inhibitor (DHFR inhibitor) is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate. Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage.
How is HMG-CoA reductase activated?
Regulation of HMG-CoA Reductase
First by regulation of transcription of the reductase gene, which is activated by sterol regulatory element binding protein, a protein that binds to the promoter of the HMGR gene when cholesterol levels fall.
Where does HMG-CoA reductase work?
Introduction. Also known as statins, HMG-CoA reductase inhibitors work by inhibiting the synthesis of cholesterol in the liver by the enzyme HMG-CoA reductase.
What controls HMG-CoA reductase?
Short-term regulation of HMG-CoA reductase is achieved by inhibition by phosphorylation (of Serine 872, in humans).
What are the two functions of NADP reductase?
Function. Ferredoxin: NADP+ reductase is the last enzyme in the transfer of electrons during photosynthesis from photosystem I to NADPH. The NADPH is then used as a reducing equivalent in the reactions of the Calvin cycle.
What is the substrate for reductase?
Aldehydes that contain an aromatic ring are generally excellent substrates, consistent with crystallographic data which suggest that aldose reductase possesses a large hydrophobic substrate binding site.
What is the function of enzyme peptidase?
Peptidase Mechanism and Function
Peptidase breaks protein compounds down into amino acids by leaving the peptide bonds within proteins by hydrolysis. This means that water is used to break the bonds of protein structures.
What is the role of HMG-CoA reductase in the liver?
HMG-CoA reductase (HMGR) catalyzes the rate-controlling step in cholesterol production. This enzyme is highly expressed in the liver, where it is subject to extensive hormonal and dietary regulation.
How do statins inhibit HMG-CoA reductase?
Statins competitively inhibit the HMG-CoA reductase enzyme. Statins bind to the active site of the enzyme and change its structure. As the structure of the enzyme is changed, it cannot bind with the receptor, thus its activity is reduced.
How does inhibition of HMG-CoA reductase cause lowering of cholesterol and LDL levels?
Recently, a new class of lipid-lowering drugs, HMG CoA reductase inhibitors, have been introduced. These drugs act by decreasing liver cholesterol synthesis resulting in up-regulation of LDL receptors, increased clearance of LDL from plasma, and diminution of plasma LDL levels.
What class of antibiotic is trimethoprim?
Trimethoprim is a prescription medicine used to treat the symptoms of bacterial infections. Trimethoprim may be used alone or with other medications. Trimethoprim belongs to a class of drugs called Antibiotics, Other.
Which of the following enzymes is inhibited by methotrexate?
Methotrexate is an antimetabolite, which, by inhibiting the enzyme dihydrofolate reductase, inhibits the synthesis of the purines and pyrimidines that are necessary for nucleic acid synthesis.
How is trimethoprim metabolism?
Approximately 10-20% of an ingested trimethoprim dose is metabolized, primarily in the liver, while a large portion of the remainder is excreted unchanged in the urine.
How do Antifolates work?
Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate’s actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).
Which drug group inhibits folic acid synthesis?
Sulfonamides and trimethoprim inhibit synthesis of folate at two different sites. The sulfonamides are structurally similar to PABA and block the incorporation of PABA into dihydropteroic acid. Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase.
What is the mechanism of action of sulfonamide?
Sulfonamides inhibit multiplication of bacteria by acting as competitive inhibitors of p-aminobenzoic acid in the folic acid metabolism cycle. Bacterial sensitivity is the same for the various sulfonamides, and resistance to one sulfonamide indicates resistance to all. Most sulfonamides are readily absorbed orally.