Unit 3 Purine & Pyrimidine Met

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1

Bases, Nucleosides, Nucleotides

Bases include the purines and pyrimidines. When they are attached to a sugar then become nucleosides, and when that is attached to a 1 + phosphate groups, then they are nucleotides.

2

Purines and Pyrimidines

Genetic code; ATP for biosynthesis, ion transport, muscle contraction; GTP in protein synthesis; UDP glucose & UDP glucuronic acids in polysaccharides and oligosaccharides, and detox; NAD, FAD, CoA

3

Adenosine and Caffeine

Adenosine inhibitis CNS while caffeine activates CNS

4

AMP, cAMP, cGMP

GTP

stimulate AMPK, PKA, and PKG respectively

G protein activity

5

Dietary uptake of purines and pyrimidines fulfills x% daily needs.

< 1%

6

What are the 6 different precursors of purine biosynthesis? How many high energy bonds does it take to form one purine?

Glu X2, N Formyl FH4 X2, Gly, CO2, Asp. 6 high energy bonds

7

De novo synthesis of purines takes place? Transport of bases and nucleosides?

Mainly in the liver, but also in the brain. RBCs transport bases and nucleosides

8

Synthesis of Inosine Monophosphate

10 Steps; 4 enzymes use ATP; N-formyl FH4- requires dietary folate (inadequate = megaloblastic anemia); first purine nucleotide; base = hypoxanthine

9

First committed step in Purine Biosynthesis

Synthesis of Phosphoribosylamine by Glutamine phosphoribosyl amidotransferase (GPA); Highly regulated; PRPP & Gln below Km

10

Adenosine Monophosphate Synthesis

IMP + Asp = adenylosuccinate (by adenylosuccinate synthetase) - fumarate = AMP (by adenylosuccinase w/ GTP)

11

Guanosine Monophosphate Synthesis

IMP DeH = xanthosine monophosphate (XMP) + Gln = GMP (by GMP synthetase w/ ATP)

12

Phosphorylation of AMP and GMP

Nucleoside monophosphate kinase forms ADP & GDP

Nucleoside diphosphate kinase forms ATP & GTP

13

Regulated Steps

GPA by end products: A(G)MP, DP, TP

PRPP synthetase by ADP & GDP

IMP DeH by GMP & Adenylosuccinate synthetase by AMP

Reciprocal regulation: GTP needed to make ATP et vice versa

14

Purine Salvage Pathway

hypoxanthine-guanine phosphorybosyltransferase (HGPRT): reattaches free purines to PRPP (activated ribose)- *major nucleotide generation pathway for lymphocytes
-PRPP + free base -> nucleotide + PPi

15

Purine Nucleoside Phosphorylase (PNP)

Catalyzes phosphorolysis of N-glycosidic bond: Guanosine -> Guanine, Inosine -> hypoxanthine

Deficiency leads to compromise of T-cell immunity

16

Deficiency of HGPRT

Treatment?

Lesch-Nyhan syndrome- disrupted purine salvage pathway, inc. uric acid, x-linked recessive, mental retardation, self-mutilation, hyperuricemia- gout. Treatment: allopurinol before or after attack

17

Purine Deamination

Adenosine -> Inosine (by adenosine deaminase ADA1)

AMP -> IMP (by AMP deaminase)

18

ADA1 Deficiency

Causes severe combined immunodeficiency disease (SCID): accumulation of dATP = inhib ribonucleotide diphosphate reductase- impaired lymphocyte proliferation & dec. deoxyribonucleotides

19

ADA1 Deficiency Cont.

no T-cells or B-cells, 1 in 100k births, delay of detection up to six months

20

AMP Deaminase Deficiency

results in muscle fatigue during exercise due to fumerate not generated by the cycling of AMP to IMP and back to AMP. Other enzymes in cycle: AS synthetase & AS lyase. 1:50 - 1:40k people

21

AMP Deaminase

Drives 2ADP -> ATP + AMP by AMP + H2O -> IMP + NH3

22

Pyrimidine Synthesis

Base synthesized first; produced from Asp & carbamoyl phosphate; 1st 3 enzymes on CAD

23

CAD

Crbamoyl phosphate synthetase II, Asp transcarbamoylase, and Dihydro-orotase

24

Carbamoyl phosphate

derived from CO2 and Gln, catalyzed by carbamoylphosphate synthetase II (CPS II) Urea cycle (CPS I in cytosol, Gln- source of nitrogen)

25

CPS II

Regulated step inhibited by UTP, activated by PRPP, phosphorylation increases sensitivity to activation (occurs during S-phase)

26

2nd Enzyme Urea Cycle Deficiency

Carbamoyl phosphate leaked into cytoplasm, bypass of CPS II, orotic aciduria

27

Folate Deficiency

results in anemia (macrocytic or megaloblastic); converts dUMP to dTMP

28

UMP synthase

2 enzyme activities converting orotic acid to UMP

29

UMP synthase Deficiency

hereditary orotic aciduria, block of pyrimidine synthesis leading to growth retardation. Treatment: oral uridine, which gets converted to UMP

30

Ribonucleotide reductase (RR)

CDP -> dCDP & UDP -> dUDP

31

thymidylate synthase

N5, N10-methylene-THF used to methylate dUMP to produce dTTP

32

Anticancer Drugs

5-fluorouracil inhibits thymidylate synthase- no dTMP synth

Methotrexate inhibits dihydrofolate reductase: antifolate drug- treats cancers & autoimmune diseases: prevents FH2 -> N5, N10-methylene-THF

33

Pyrimidine Degradation

deamination: cytosine -> CO2, NH4, beta-alanine; thymine -> CO2, beta-aminoisobutyrate Products excreted in urine

34

Pyrimidine Salvage Pathway

pyrimidine phosphorylase: bases -> nucleoside: Thymine phosphorylase: + deoxyribose residue
Nucleoside kinase: nucleoside -> nucleotide (inefficient pathway)

35

NDPs are substrates for?

dNDPs!

36

Ribonucleotide reductase

reduction of ribose to deoxyribose; 2 allosteric sites One site controls specificity and the other controls activity- ATP activated & dATP inhibited; requires thioredoxin, NADPH reduces oxidized thioredoxin.

37

Regulation of Ribonucleotide Reductase

ATP activates CDP -> dCDP & UDP -> dUDP. dUDP is converted to dTTP. dTTP promotes GDP -> dGDP -> dGTP. dGTP promotes ADP -> dADP -> dATP dATP inhibits the enzyme

38

Purine Degradation

Mainly in liver; salvage enzymes used for reactions; produces guanine & hypoxanthine, which are converted to xanthine, which is converted to uric acid and excreted in urine

39

Xanthine oxidase- DeH

Contains 2 molybdenum atoms; converts hypxanthine to xanthine and xanthine to uric acid; H2O2 reaction product

40

Uric acid

half of antioxidant capacity of blood plasma, uric acid forms urate at physiological pH- not very soluble in aq soln, normal concentration close to solubility constant

41

Uric acid excretion

most reabsorbed in proximal tubule, 80% in urine from distal tubule secretion; higher in males; reabsorption stimulated by organic acids (ie lactic acid), 75% leaving body is in urine, 25% passes into intestinal lumen

42

Hyperuricemia Factors

Sex, Obesity, Diet (high protein diet & high alcohol consumption), Genetic factors

43

gout

metabolic arthritis, monosodium urate crystal deposition, overproduction of uric acid (primary gout), or underexcretion (most common) Treatment: Attack- NSAIDs, Prevention- allopurinol, limit alcohol, uricosuric drugs- increase excretion

44

Xanthinuria

mutation of xanthine dehydrogenase, aldehyde oxidase, or molybdenum cofactor. Low uric acid, high xanthine excretion, renal xanthine stones

45

Allopurinol

structural analogue of hypxanthine, converted to oxypurinol which inhibits xanthine oxidase, degraded purine spread over hypxanthine, xanthine, and uric acid