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ATP?. Depends on the system…. 1 ATP – Glucose to G-6-P   Ribose-5-P 1 ATP – But 2 high energy bonds to get to PRPP 4 ATP – In vertebrates to get onto IMP from PRPP 5 ATP – In prokaryotes to get onto IMP from PRPP

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Presentation Transcript
slide1

ATP?

Depends on the system….

slide4

1 ATP – Glucose to G-6-P   Ribose-5-P

1 ATP – But 2 high energy bonds to get to PRPP

4 ATP – In vertebrates to get onto IMP from PRPP

5 ATP – In prokaryotes to get onto IMP from PRPP

The pentose phosphate shunt can go back through glycolytic pathways, utilizing another ATP (Fructose-6-P to Fructose-1,6,bisP and then onto Ribose-5-P), but not necessary to generate Ribose-5-P)

slide6

LEARNING OBJECTIVES

  • Nomenclature of pyrimidines*
  • Key features of biosynthetic pathway and origin of atoms in pyrimidine ring
  • Basis of chemotherapy using nucleotide analogs

*Key words are highlighted in yellow

pyrimidine synthesis
Pyrimidine Synthesis
  • The pyrimidine ring is completely synthesized, then attached to a ribose-5-phosphate donated by PRPP
  • Source of carbons and nitrogens less diverse than with purines.
slide10

Urea Synthesis

Pyrimidine Synthesis

slide11

Carbamoyl Phosphate Synthase and Channeling of Intermediates

Miles et al. J. Biol. Chem. 274, 12193-12199 (1999)

slide12

Enzymatic functions from one large protein (215,000 Mr)

Enzymatic functions from one large protein

slide13

What to Know

Compare and contrast CPS I and CPS II

CPSII, aspartate transcarbamoylase, and dihydroorotase are three enzymatic functions in one protein.

Oratatephosphoribosyltransferase and OMP decarboxylase are two enzymatic functions in one protein. Deficiency leads to Orotic Aciduria. Know symptoms and how to treat.

Orotate is made and then attached to a PRPP.

slide14

Nitrogen Donor

(again!)

UMP

UDP

UTP

Uridine monophosphate kinase

Uridine diphosphate kinase

Uridine

Cytidine

slide15

Thymidylate synthase is a major target for anti-cancer therapy.

5-fluorouracil

Methotrexate also

inhibits this reaction

See Figs 26.25-26.27 in reading

for more details

slide18

AMP

ADP

ATP

Adenosine

monophosphate

kinase

Adenosine

diphosphate

kinase

GMP

GDP

GTP

Guanosine

monophosphate

kinase

Guanosine

diphosphate

kinase

UDP

UTP

Uridine monophosphate kinase

Uridine

diphosphate

kinase

dUMP

dUDP

CTP

Thymidylate synthase

Thymidine

diphosphate

kinase

dTMP

dTDP

dTTP

Thymidine monophosphate kinase

De novo purine synthesis

IMP

De novo pyrimidine synthesis

UMP

slide21

Logic For Deoxynucleotide Synthesis

(Fig 26.24) in reading

  • High [ATP], plenty of energy, ok to make DNA
  • High [ATP] means the ribonucleotide reductase is active (ON)
  • ATP in specificity site S favors CDP or UDP in catalytic site C  [dCDP] and [dUDP] ↑
  • dCDP and dUDP become metabolized to dTTP (thus justifying the synthesis of dUMP even though it does not get incorporated into DNA)
  • As [dTTP]↑, it will begin to occupy specificity site favoring GDP in catalytic site, thus leading to [dGP]↑  [dGTP]↑
  • As [dGTP]↑ it begins to occupy specificity site and thus favor ADP in catalytic site, leading to [dADP]↑  which will replace ATP in activity site and turn enzyme off
uracil analogues in cancer therapy
Uracil Analogues in Cancer Therapy

Uracil

5-fluorouracil

β-D-arabinofuranosylcytosine (Ara-C)

slide23

Thymidylate

Synthase

dUMP

dTMP

O

F

HN

O

N

2-O3POH2C

dFUMP

O

HO

  • Cancer Therapy with 5-fluorouracil
  • 5-FU is typically given with thymidine to boost its effectiveness
  • 5-FU is converted to dFUMP
  • dFUMP inhibits Thymidylate synthase
  • In cancer cells, 5-FU is also incorporated into RNA
  • 5-FU in RNA is detrimental to cancer cells
  • Inhibition of Thymidylate synthase is detrimental to both cancer and normal cells
  • So, administration of thymidine protects both normal and cancer cells, but 5-FU in cancer cells kill them
thymine analogues in cancer therapy
Thymine Analogues in Cancer Therapy

Thymidine

Bromodeoxyuridine

Trifluorothymidine

purine analogues in cancer therapy
Purine Analogues in Cancer Therapy

Hypoxanthine

6-mercaptopurine

6-thioguanine

Purines are used as free bases or nucleosides, as nucleotides are poorly transported across the membrane.