DIHIDROFOLATO REDUCTASA PDF

Molecular Psychiatry 11 4: Two isolates were obtained from the cerebrospinal fluid of HIV-infected patients with cerebral toxoplasmosis. A collection of writing tools that cover the many facets of English and French grammar, style and usage. Current Pharmaceutical Design 14 Chemical Record 2 1: Wiwanitkit V Jul Algunas mutaciones en este gen se encuentran asociadas con deficiencias en la actividad de la metilentetrahidrofolato reductasa. This study sought to perform cloning and sequencing of the dihydrofolate reductase dhfr and deductasa dhps genes of the reference Rh strain and two Colombian isolates of Toxoplasma gondii.

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The high flexibility of Met20 and other loops near the active site play a role in promoting the release of the product, tetrahydrofolate. Specifically, the catalytic reaction begins with the NADPH and the substrate attaching to the binding site of the enzyme, followed by the protonation and the hydride transfer from the cofactor NADPH to the substrate.

However, two latter steps do not take place simultaneously in a same transition state. Asp27 plays a critical role in the catalytic mechanism by helping with protonation of the substrate and restraining the substrate in the conformation favorable for the hydride transfer.

In addition, an extra distorted conformation of Met20 was defined due to its indistinct characterization results. Thus, the next round of reaction can occur upon the binding of substrate.

It is a homotetramer that possesses the symmetry with a single active site pore that is exposed to solvent[null. The much lower catalytical kinetics show that hydride transfer is the rate determine step rather than product THF release. However, the flexibility of p-aminobenzoylglutamate tail of DHF was observed upon binding which can promote the formation of the transition state.

Because tetrahydrofolate, the product of this reaction, is the active form of folate in humans, inhibition of DHFR can cause functional folate deficiency. However, resistance has developed against some drugs, as a result of mutational changes in DHFR itself.

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. These three are widely used as antitumor and antimicrobial agents. Regardless, trimethoprim and sulfamethoxazole in combination has been used as an antibacterial agent for decades.

DHFR is one such target. A regimen of fluorouracil , doxorubicin , and methotrexate was shown to prolong survival in patients with advanced gastric cancer. Dihydrofolate reductase from Bacillus anthracis BaDHFR a validated drug target in the treatment of the infectious disease, anthrax.

BaDHFR is less sensitive to trimethoprim analogs than is dihydrofolate reductase from other species such as Escherichia coli , Staphylococcus aureus , and Streptococcus pneumoniae.

A structural alignment of dihydrofolate reductase from all four species shows that only BaDHFR has the combination phenylalanine and tyrosine in positions 96 and , respectively.

These cells are transfected with a plasmid carrying the dhfr gene and the gene for the recombinant protein in a single expression system , and then subjected to selective conditions in thymidine-lacking medium. Only the cells with the exogenous DHFR gene along with the gene of interest survive. Dihydrofolate reductase has been shown to interact with GroEL [48] and Mdm2.

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