Chapter 18

Question 1

What are nucleotides needed for?

Answer 1

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

Question 2

What are two way nucleotides are made?

Answer 2

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)

Question 3

What is Lesch Nyhan disease?

Answer 3

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

Question 4

What are the steps of the nucleotide synthesis pathways?

Answer 4

Question 5

How are pyrimidines synthesized?

Answer 5

synthesized de novo in cyotplasm from aspartate, CO2, glutamine

cytoplasmic carbamoyl phosphate synthetase

Question 6

What is orotic aciduria?

Answer 6

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

Question 7

What is the difference between the two orotic acidurias?

Answer 7

hyperammonemia

–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

Question 8

What are the steps of de novo pyrimidine sythesis?

Answer 8

Question 9

What is the end product of pyrimidine synthesis?

Answer 9

UMP

conversion of UMP to dTMP

via ribonucleotide reductase, thymidylate synthase, and dihydrofolate reductase

–targest of antineoplastic drugs

Question 10

What is cotrimoxazole?

Answer 10

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

Question 11

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

Answer 11

Question 12

What is ribonucleotide reductase?

Answer 12

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

Question 13

What is pyrimidine catabolism?

Answer 13

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

Question 14

What is purine synthesis?

Answer 14

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

Question 15

How do parasites and protozoans make purines?

Answer 15

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

Question 16

What occurs with purine catabolism?

Answer 16

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)

Question 17

When do excess nucleoside monophosphates accumulate?

Answer 17

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

Question 18

How important are salvage enzymes?

Answer 18

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

Question 19

What is adenosine deaminase deficiency (ADA)?

Answer 19

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

Question 20

What happens with treatment of large tumors?

Answer 20

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

Question 21

What is gout?

Answer 21

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

Question 22

What is hyperuricemia?

Answer 22

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

Question 23

What is the function of allopurinol?

Answer 23

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

Question 24

What conditions are accompanied by hyperuricemia and gout?

Answer 24

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

Question 25

What is Lesch Nyhan syndrome?

Answer 25

x linked recessive conditoin

near complete deficiency of HGPRT activity

mental retardation

spastic cerebral palsy with compulsive biting of hands and lips

hyperuricemia

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