What is DHFR and why is it important

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. … Alterations in DHFR expression can be due to polymorphisms in the DHFR gene.

What can DHFR be used for?

DHFR can be targeted in the treatment of cancer and as a potential target against bacterial infections. DHFR is responsible for the levels of tetrahydrofolate in a cell, and the inhibition of DHFR can limit the growth and proliferation of cells that are characteristic of cancer and bacterial infections.

What is the role of tetrahydrofolate?

Tetrahydrofolate has a role in nucleic and amino acid synthesis. … Tetrahydrofolate is used to treat topical sprue and megaloblastic and macrocytic anemias, hematologic complications resulting from a deficiency in folic acid.

How does methotrexate work DHFR?

Methotrexate inhibits DHFR with a high affinity, thus reducing the amount of tetrahydrofolates required for the synthesis of pyrimidine and purines. Consequently, RNA and DNA synthesis is stopped and the cancer cells die.

Which are DHFR inhibitors?

A dihydrofolate reductase inhibitor (DHFR inhibitor) is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate.

What reaction does DHFR catalyze include the reactants and products?

Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate (DHF), yielding tetrahydrofolate (THF), an important reaction in the folate cycle, which supplies one-carbon units for the biosynthesis of deoxythymidine monophosphate (dTMP), and for reactions involved in the biosynthesis of …

What is DHFR gene?

DHFR (Dihydrofolate Reductase) is a Protein Coding gene. Diseases associated with DHFR include Megaloblastic Anemia Due To Dihydrofolate Reductase Deficiency and Megaloblastic Anemia. Among its related pathways are Folate Metabolism and E2F mediated regulation of DNA replication.

What should you avoid while taking methotrexate?

What should I avoid while taking methotrexate? Avoid drinking alcohol. It may increase your risk of liver damage. Do not receive a “live” vaccine while using methotrexate, or you could develop a serious infection.

How does methotrexate bind to DHFR?

Thus the mechanism of methotrexate binding to DHFR involves multiple steps and protein conformational changes. Dihydrofolate reductase (DHFR) catalyzes the reaction of 7,8-dihydrofolate and NADPH to form 5,6,7,8-tetrahydrofolate and NADP+. … Because of its metabolic importance, DHFR has been extensively studied.

How does methotrexate suppress inflammation?

The way methotrexate works for inflammatory conditions is less clear. But we know it has a range of effects on DNA synthesis and immune signalling, which are thought to reduce the inflammation. In rheumatoid arthritis, methotrexate reduces inflammation and damage to joints.

Article first time published on askingthelot.com/what-is-dhfr-and-why-is-it-important/

How is Tetrahydrofolate important to purine synthesis?

In turn, tetrahydrofolate serves as the carrier of various one-carbon groups that are added to, or abstracted from, metabolites such as histidine, serine, methionine, purines, and thymidylate. … Two separate steps in the biosynthesis of purines involve the addition of a formyl group to effect ring closure.

Is Tetrahydrofolate the same as folic acid?

Folate and folic acid are terms that identify vitamin B9. Folate actually refers to the tetrahydrofolate (THF) derivative found naturally in fresh fruits, vegetables and beans. Folate is a natural product. Folic acid is the oxidized synthetic form derived from petroleum and used in supplements, beverages and foods.

What are some good food sources of folate?

  • Dark green leafy vegetables (turnip greens, spinach, romaine lettuce, asparagus, Brussels sprouts, broccoli)
  • Beans.
  • Peanuts.
  • Sunflower seeds.
  • Fresh fruits, fruit juices.
  • Whole grains.
  • Liver.
  • Seafood.

What does DHFR stand for?

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 mechanism of action for methotrexate?

Methotrexate inhibits dihydrofolate reductase, preventing the reduction of dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4), leading to nitric oxide synthase uncoupling and increased sensitivity of T cells to apoptosis, thereby diminishing immune responses.

What is the molecular weight of DHFR?

The molecular weight of the His-Tag DHFR protein, as resolved on a denaturing SDS gel, is 24 kDa.

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.

What is the most reduced form of Tetrahydrofolate?

Hence, folate can exist in various forms namely N10-formyl THF (most oxidized form), N5, N10-methynyl THF, N5, N10-methylene THF, and N5-methyl THF (most reduced form). All these different forms carrying these single carbon groups are collectively known as the “one-carbon pool”.

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 are the side effects of methotrexate?

  • dizziness.
  • drowsiness.
  • headache.
  • swollen, tender gums.
  • decreased appetite.
  • reddened eyes.
  • hair loss.

How does Methotrexate inhibit purine synthesis?

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.

Does methotrexate shorten your life?

The results resoundingly confirm prior studies, finding methotrexate use for RA associated with a 70% reduction in mortality (or a mere 5% less after adjusting for the propensity to treat). The mortality risk was not affected by likelihood to withdraw methotrexate shortly before death.

Can you be in the sun while taking methotrexate?

Methotrexate is often listed as causing sun sensitivity. However, methotrexate is not, in fact, a sun sensitizing drug, but rather produces a reaction called radiation recall. Areas where patients have had sunburns in the past may react again after starting methotrexate.

Why should you not touch methotrexate?

Even touching or inhaling the dust from the tablet can allow the medicine to get into the body. Methotrexate goes into sperm, so it’s important that a man taking it doesn’t get his partner pregnant. Whether you’re male or female, you must use birth control while taking methotrexate.

What are the most common side effects of methotrexate?

  • feeling sick.
  • headaches.
  • vomiting.
  • diarrhoea.
  • shortness of breath.
  • mouth ulcers.
  • minor hair loss and hair thinning.
  • rashes.

What is the safest drug to treat rheumatoid arthritis?

Hydroxychloroquine is an antimalarial drug which is relatively safe and well-tolerated agent for the treatment of rheumatoid arthritis.

Can I take vitamin D with methotrexate?

No interactions were found between methotrexate and Vitamin D3. This does not necessarily mean no interactions exist. Always consult your healthcare provider.

What is purine synthesis?

Purine synthesis is a ten-step process that requires ribose-5-phosphate from the PPP, glycine and formate from the serine/glycine synthesis pathway, glutamine, and TCA cycle-derived aspartate. From: Pathobiology of Human Disease, 2014.

How Tetrahydrofolate is formed?

Human synthesis Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate. It is converted into 5,10-methylenetetrahydrofolate by serine hydroxymethyltransferase.

How is folate used in nucleotide metabolism?

Role of Folate in Metabolism Folates serve as coenzymes in many biologic reactions, including (1) the synthesis of nucleotides for DNA and RNA synthesis, (2) the interconversion of serine and glycine, (3) the generation of methionine, and (4) the methylation of a vast array of biologic molecules.

What is homocysteine and what is its function?

Homocysteine is an amino acid. Vitamins B12, B6 and folate break down homocysteine to create other chemicals your body needs. High homocysteine levels may mean you have a vitamin deficiency. Without treatment, elevated homocysteine increases your risks for dementia, heart disease and stroke.