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Flashcards in Chapter 18 Deck (26)

What are nucleotides needed for?

DNA and RNA synteshsis and energy transfer

ribose 5 phosphate for nculeotide syntehsis is derived from hexose monophopshate shunt

--acited by the addition of pyrophosphate from ATP, forming phosphoribosyl pyrophosphate (PRPP) using PRPP synthase


What are two way nucleotides are made?

de novo synthesis: in liver; purine and pyrimidines are synthesized from samller precusors and PRPP is added

salvage pathways: preforemd purine and pyrimidine based converted into nucleotides

--bases for salvage enzymes may arise from synthesis in liver and transport to other tisssues or digestion of endogenous nucleic acids (cell death, RNA turnover)


What is Lesch Nyhan disease?

enzyme for purine salvage (hypoxanthine guanine phosphoribosyl pyrophosphate transferase, HPRT) is absent

salvage pathway is essential for adequate nucleotide syntehsis

CNS deterioration, mental retardation, spastic cerebral palsy assocaited with compulsive self-mutilation

cells in basal ganglia of brain (fine motor control) normally have high HPRT activity

hyperuricemia beacuase purines can't be salvaged


What are the steps of the nucleotide synthesis pathways?


How are pyrimidines synthesized?

synthesized de novo in cyotplasm from aspartate, CO2, glutamine

cytoplasmic carbamoyl phosphate synthetase


What is orotic aciduria?

severe anemia, megoblastic

urine contains crystalline residue--orotic aicd

treatment: uridine--bypassing defect in pyrimidine pathway

--salvaged to UMP which feedback inhibits carbamoyl phosphate synthase 2 preventing orotic acid formation

autosomal recessive disorder

defect in uridine monosphosphate (UMP) synthase: includes orotate phosphoribosyltransferase and orotidine decarboxylase

--lack of pyrimidines impairs nucleic acid syntehsis needed for hematopoiesis--megoblastic anemia)

oroti acid accumulates and spills in urine--orotic acid crystals and orotic acid urinary obstruction



What is the difference between the two orotic acidurias?


--no megaoblastic anemia

--pathway: urea cycle

--enzyme deficient: OTC
megaloblastic anemia

--no hyperammonemia

--pathway: pyrimidine synthesis

--enzyme deficient: UMP synthase

folate deficiency: megaloblastic anemia but no orotic aciduria


What are the steps of de novo pyrimidine sythesis?


What is the end product of pyrimidine synthesis?


conversion of UMP to dTMP

 via ribonucleotide reductase, thymidylate synthase, and dihydrofolate reductase

--targest of antineoplastic drugs


What is cotrimoxazole?

contains synergistic antibiotics sulfamethoxazole and trimethoprim--inhibits different steps in prokaryotic syntehsis of tetrahydrofolate


What are the important enzymes of pyrimidine synthesis? What is their function and the drug that acts on them?


What is ribonucleotide reductase?

required for formation of deoxyribonucleotides for DNA synthesis

all four nucleotide substrates must be disphotes

dADP and dATP strongly inhibit ribonucleotide reductase

hydroxyurea--anticancer drug--blocks DNA synthesis indirectly by inhibiting ribonucleotide reductase


What is pyrimidine catabolism?

completely catabolized (NH+ is produced) or recycled by pyrimidine salvage enzymes


What is purine synthesis?

purines syntehsized de novo beginning with PRPP

most important enzyme: PRPP amidotransferase

catalyzes first and rate lmiting reaction of pathwya

--inhibited by three purine nculeotide end products: AMP, GMP, IMP

--drugs allopurinol (gout) and 6 mercaptopurine (antineoplastic) inhibit PRPP amidotransferase

--drugs are purine analogs that must be converted to nucleotides by HGPRT within cells

--amino acids glycine aspartate and glutamine are used in purine synthesis

--tetrahydrofolate required for syntehsis of all purines

--inosine monophosphate (contains purine base hypoxanthine) is precursor for AMP and GMP


How do parasites and protozoans make purines?

protzoan and multicellular parasites and many obligate parasites (Chlamydia) cna't syntehsize purine de novo becuase they lack necessary genes in purine pathway

-have elaborate salvage mechanismsfor acquiring purins from host to syntehsize their own nucleic acids to grow


What occurs with purine catabolism?

excess purine nucleotides or those released from DNA nad RNA by nculeases are cataoblzied first to nucleosides (loss of Pi) then to free purine bases (release of ribose or deoxyribose)


When do excess nucleoside monophosphates accumulate?

RNA is normally digested by nucleases (mRNAs and other types of RNAs are continuously turned over in nromal cells)

dying cells release DNA and RNA which is digested by nucleases

concentration of free Pi decerases as it may in galacosemia, hereditary fructose intolerance, and glucose 6 phosphatase deficiency


How important are salvage enzymes?

salvage enzymes recycle normally about 90% of purines, 10% are converted tourice acids and excreted in urine

when purine catabolism is increased significantly person is at risk for devleoping hyperuricemia and gout



What is adenosine deaminase deficiency (ADA)?

autosomal recessive disorder

produces severe combined immunodeficiency (SCID)

lacking both B and T cells functoin 

children are multiply infected with many organisms (Pneumocystis carinii, Candida) and don't survive without treatment

treatment: enzyme replacement therapy and bone marrow transplant

high levels of dATP accumulate in red cells and inhibit ribonucleotide reductase--inhibiting production of other essential deoxynulceotide precursors for DNA synthesis

thought that impaired DNA synthesis contributes to dysfunction of B and T cells


What happens with treatment of large tumors?

treatment of large tumors with chemotherapeutic regimens or radiation presents excessive excretion of uric acid, reuslting in gout

cuase of excessive uric acid is destruction of cancer cell's nucleic acid into purines undergoing turnover


What is gout?

acute gouty arthritis

most often in males

results from precipitation of monosodium urate crystals in joints

crystals (negatively birefringent and needle shaped) initiate neutrophil mediated and acute inflammation (first affecting big tow)

chronic gout may manifest over time as tophi (deposits of monosodium urate) develop in soft tissue around joints, leading to chronic inflammation involving granulomas

--acute attacks of gout are treated wth colchicine or indomethacin to reduce inflammation

-chronic hyperuricemia becuase of underexcetion is treated with uricosuric drug (probenecid)

overproduction of uric acid and chronic gout are treated wtih allopurinol


What is hyperuricemia?

may be produced by overproduction of uric acid or underexcretion of uric acid by kidneys

may progress to acute and chronic gouty arthritis if uric acid (monosodium urate) is deposited in joints and surrounding soft tissues--where is causes inflammation

uric aid is produced from excess endogenous purines and from dietary purines (digestion of nucleic acid in intestine) by intestinal epithelial

--transported in blood to kidneys for excretion in the urine


What is the function of allopurinol?

inhibits xanthine oxidase and reduce purine syntehsis by inhibiting PRPP aminotranferase (provided HGPRT is active)


What conditions are accompanied by hyperuricemia and gout?

Lesch-Nyhan syndrome (no purine salvage)

partial deficiency of HGPRT

alcholism (lactate and urate compete for same transprot system inkidney

glucose 6 phosphatase deficiency

hereditary fructose intolerance

galactose 1 phosphate uridyl transferase deficiency (galactosemia)

--last 2 disease, phosporylated sugars accumulate decreasing the avialable Pi and increasing AMP (which can't be phosphorylated to ADP and ATP)--excess AMP is converted to uric acid


What is Lesch Nyhan syndrome?

x linked recessive conditoin

near complete deficiency of HGPRT activity

mental retardation

spastic cerebral palsy with compulsive biting of hands and lips


death often in first decade

--mutations in HGPRT gene on X chromosome: point mutation, complete deletion

--mutation results in increased Km for hypoxanthine and guanine for enzyme--mutation that cuase the encoded enzyme to have a short half life

tiny orange colored particles in diapers

uric acid in urine

--wihtout salvaging of hypoxanthine and guanine by HGRT, purines are shunted toward the excretion pathway

--compounded by lack of regulatory control of PRPP aminotransferase in purine sytnehsis pathway, resulting in sytheshsis of even more purines in body

large amounts of urate will cause crippling gouty arthritis and urate nephorphathy

renal failure is usually cause of death

treatment: allopurinol, ease amount of urate deposits formed