inorganic phosphate by which uracil and thymine bases are scavengedDefect in HGPRT: Lesch-Nyhan Syndrome●Arises through x-linked recessive mutation●Presents with uncontrolled severe movement (spasticity), severe mental deficiency,self-mutilation (i.e. biting fingers off), hyper-aggression, severe gout, and kidneystones●Loss of HGPRT results in increase of both serum PRPP and serum urate, thecatabolism product of purine bases○This increase in serum urate gives rise to gout and kidney stones○Salvage pathway is not working, so there is an increase in the purine de novopathwayThymidylate Biosynthesis
●●Deoxynucleotides are made from Ribonucleosides Di-Phosphates●The 2’ hydroxyl is reduced●Then, the diphosphate is phosphorylated to make a triphosphate●However, the production of Thymidine Triphosphate (TTP) requires a folatederivative, so it requires a special pathway●We 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 makethymidylate●The products of this reactions are: thymidine monophosphate (TMP) anddihydrofolate●And, N5-N10-methylene-tetrahydrofolate is converted to dihydrofolate●For the enzyme to become active again, the N5-N10-methylene-tetrahydrofolatemust be reconstituted○This is done by action of the enzyme: tetrahydrofolate reductase○The enzyme reduces dihydrofolate to tetrahydrofolate○Electrons are used from NADPH○Then, a methyl group from serine is used to regenerate N5-N10-methylenetetrahydrofolate○This is the unique cycle needed for producing TMP, and not any of the theribonucleotides○Targeting this cycle can shut down DNA synthesis, so potentchemotherapeutics are used for thisChemotherapeutics●Fluorouracil○Is 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 synthase●Aminopterin and Methotrexate○Both serve to inhibit the dihydrofolate reductase because they look a lotlike dihydrofolate○So they can compete for the active site○So, aminopterin and methotrexate are competitive are competitive inhibitorsof dihydrofolate reductaseSulfa Drugs and Bacteria●Folic acid is necessary for the production of thymidylate●We take in folic acid via our diet; we can’t make it ourselves●Bacteria can make folic acid through the use of PABA, and aminobenzoate●Sulfa drugs can be used to block folic acid production in bacteria○These are antibiotics that look a lot like PABA○So sulfonamide can act as a competitive inhibitor of the enzyme that makesfolic acid●By blocking folic acid production, we block thymidylate production, thereby blockingreplication of bacteriaRibonucleotide Reductase●This is the enzyme that catalyzes the reduction of the 2’ Hydroxyl●Just 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
