Course Hero Logo

Inorganic phosphate by which uracil and thymine bases

Course Hero uses AI to attempt to automatically extract content from documents to surface to you and others so you can study better, e.g., in search results, to enrich docs, and more. This preview shows page 40 - 44 out of 119 pages.

inorganic phosphate by which uracil and thymine bases are scavengedDefect in HGPRT: Lesch-Nyhan SyndromeArises through x-linked recessive mutationPresents with uncontrolled severe movement (spasticity), severe mental deficiency,self-mutilation (i.e. biting fingers off), hyper-aggression, severe gout, and kidneystonesLoss of HGPRT results in increase of both serum PRPP and serum urate, thecatabolism product of purine basesThis increase in serum urate gives rise to gout and kidney stonesSalvage pathway is not working, so there is an increase in the purine de novopathwayThymidylate Biosynthesis
Deoxynucleotides are made from Ribonucleosides Di-PhosphatesThe 2’ hydroxyl is reducedThen, the diphosphate is phosphorylated to make a triphosphateHowever, the production of Thymidine Triphosphate (TTP) requires a folatederivative, so it requires a special pathwayWe need deoxyuridyl monophosphate (dUMP) and the cofactorN5-N10-methylene-tetrahydrofolate (a folate, Vit B9 derivative)The folate cofactor transfers a methyl group to deoxyuridylate to makethymidylateThe products of this reactions are: thymidine monophosphate (TMP) anddihydrofolateAnd, N5-N10-methylene-tetrahydrofolate is converted to dihydrofolateFor the enzyme to become active again, the N5-N10-methylene-tetrahydrofolatemust be reconstitutedThis is done by action of the enzyme: tetrahydrofolate reductaseThe enzyme reduces dihydrofolate to tetrahydrofolateElectrons are used from NADPHThen, a methyl group from serine is used to regenerate N5-N10-methylenetetrahydrofolateThis is the unique cycle needed for producing TMP, and not any of the theribonucleotidesTargeting this cycle can shut down DNA synthesis, so potentchemotherapeutics are used for thisChemotherapeuticsFluorouracilIs a suicide inhibitor
It binds to the active site of thymidylate synthase and serves to shut itdown by covalently bonding to the enzyme that can’t be broken, to knock outthymidylate synthaseAminopterin and MethotrexateBoth serve to inhibit the dihydrofolate reductase because they look a lotlike dihydrofolateSo they can compete for the active siteSo, aminopterin and methotrexate are competitive are competitive inhibitorsof dihydrofolate reductaseSulfa Drugs and BacteriaFolic acid is necessary for the production of thymidylateWe take in folic acid via our diet; we can’t make it ourselvesBacteria can make folic acid through the use of PABA, and aminobenzoateSulfa drugs can be used to block folic acid production in bacteriaThese are antibiotics that look a lot like PABASo sulfonamide can act as a competitive inhibitor of the enzyme that makesfolic acidBy blocking folic acid production, we block thymidylate production, thereby blockingreplication of bacteriaRibonucleotide ReductaseThis is the enzyme that catalyzes the reduction of the 2’ HydroxylJust know that this enzyme is primarily regulated through allostery

Upload your study docs or become a

Course Hero member to access this document

Upload your study docs or become a

Course Hero member to access this document

End of preview. Want to read all 119 pages?

Upload your study docs or become a

Course Hero member to access this document

Term
Spring
Professor
KAGUNI
Tags

Newly uploaded documents

Show More

  • Left Quote Icon

    Student Picture

  • Left Quote Icon

    Student Picture

  • Left Quote Icon

    Student Picture