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Chapter 10. Nucleotide metabolism. Function of neucleotides. Precursors for RNA and DNA synthesis Energy substance in body (ATP) Physiological Mediators (cAMP) Components of coenzymes (NAD + ) Allosteric effectors and donor of phosphate group (phosphorylation)

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slide1

Chapter 10

Nucleotide metabolism

function of neucleotides
Function of neucleotides
  • Precursors for RNA and DNA synthesis
  • Energy substance in body (ATP)
  • Physiological Mediators (cAMP)
  • Components of coenzymes (NAD+)
  • Allosteric effectors and donor of phosphate group (phosphorylation)
  • Formation of activated intermediates

UDP-glucose, CDP-choline

section 10 2

Section 10.2

Nucleotide Synthesis and Degradation

digestion and absorption of nucleotide

Nucleoprotein

Protein

Nucleic acid

Nucleases

Nucleotide

Nucleotidase

Absorption

Phosphate

Nucleoside

Nucleosidase

Base

Ribose

Digestion and absorption of nucleotide

Blood

metabolism of purine nucleotides
Metabolism of Purine nucleotides
  • Biosynthesis of purine nucleotides

de novo synthesis

salvage pathway

AMP

GMP

1 de novo synthesis of purine nucleotides

CO2

Glycine

Aspartate

One carbon unit

One carbon unit

Glutamine

1.De novo synthesis of purine nucleotides
slide7
Characteristics of de novo synthesis of purine nucleotides

1. in cytosol

2. form IMP first, then synthesize AMP and GMP from IMP.

3. formation of purines is based on the ribosyl group of 5’-phosphoribose

slide8

AMP

ATP

PRPPK

Gln

Glutamine PRPP amidotransferase (GPRT)

Glu

AMP

GMP

PP-1-R-5-P( 5’-phosphoribose 1’-pyrophosphate, PRPP)

R-5-P

(5’-phosphoribose)

H2N-1-R-5´-P

(5´-phosphoribosyl-amine)

Gly, one carbon units, Gln, CO2, Asp involved step by step

IMP

slide9

AMP

ATP

PRPPK

Gln

Glutamine PRPP amidotransferase (GPRT)

Glu

AMP

GMP

PP-1-R-5-P( 5’-phosphoribose 1’-pyrophosphate, PRPP)

R-5-P

(5’-phosphoribose)

H2N-1-R-5´-P

(5´-phosphoribosyl-amine)

Gly, one carbon units, Gln, CO2, Asp involved step by step

IMP

regulation of de novo synthesis of purine nucleotides

_

_

_

+

+

R-5-P

PRPPK

GPAT

IMP

_

ATP

GMP

GTP

XMP

GDP

_

Adenyl-succinate

ADP

ATP

AMP

_

+

+

_

Regulation of de novo synthesis of purine nucleotides

PRPP

PRA

Adenyl-succinate

GTP

ATP

AMP

ADP

IMP

XMP

GTP

GMP

GDP

ATP

2 salvage synthesis of purine nucleotides
2. Salvage synthesis of purine nucleotides
  • Material:

PRPP, purine (conjunction)

nucleosides (phosphorylation)

  • Location:

brain and bone marrow

or

slide13

APRT

adenine+PRPP

AMP + PPi

HGPRT

hypoxanthine+PRPP

IMP + PPi

HGPRT

guanine+PRPP

GMP + PPi

Adenylate kinase

adenosine

AMP

ATP

ADP

APRT: adenine phosphoribosyltransferase

HGPRT: inosine-guanine phosphoribosyl transferase

degradation of purine nucleotides
Degradation of purine nucleotides

nucleotide

nucleosides

ribose-1-phosphate purine

salvage pathway uric acid

Nucleotidase

Nucleoside phosphorylase

slide15

IMP

Neucleo-tidase

Excretion

metabolsm of pyrimidine nucleotides
Metabolsm of pyrimidine nucleotides
  • Biosynthesis of pyrimidine nucleotides

de novo synthesis

salvage pathway

slide18
Characteristics of de novo synthesis of pyrimidine nucleotides

1. mostly in cytosol

2. form UMP first, then synthesize other pyrimidine nucleotides from UMP.

3. in the synthesis of UMP, pyrimidine ring is formed first , then combined with PRPP.

process of de novo synthesis of ump
Process of de novo synthesis of UMP
  • 1. formation of Carbamoyl phsphate (CP)

CO2 + glutamine + H2O + 2ATP

Carbamoyl phosphate synthaseⅡ (CPSⅡ)

O

O~PO32-

+ 2ADP + Pi

H2N

C

carbamoyl phosphate

slide20

The diffirents between Carbamoyl phosphate synthaseⅠ,Ⅱ

Mitochondria of liver cells

cytosol of all cells

Location

Source of nitrogen

NH3

Glutamine

N-acetylglutamate

None

Activator

Formation of pyrimidine

Function

Formation of urea

slide21

O

O~PO32-

H2N

C

carbamoyl phosphate

2. Formation of UMP

+

Aspartate

Carbamoyl aspartate

Orotate

PRPP

UMP

slide22

CTP synthase

UMPK

NDK

ATP

ADP

Gln

ATP

ATP

ADP

Glu

ADP

dUDP

dCMP

dTMP

dUMP

TMP synthase

3. Synthesis of CTP, dTMP or TMP

UDP

UTP

regulation of de novo synthesis of pyrimidine nucleotides

+

-

-

Purine nucleotides

+

-

Pyrimidine nucleotides

Regulation of de novo synthesis of pyrimidine nucleotides

ATP + CO2+ glutamine

  • Activated by substrates
  • Inhibited by products

Carbamoyl phosphate

-

aspartate

Carbamoyl aspartate

ATP + 5-phosphate ribose

PRPP

UMP

UTP

CTP

-

salvage pathway of pyrimidine nucleotides

Uracil phosphate ribosyltransferase

Uracil +PRPP

UMP+ PPi

Uridine kinase

Uracil ribonucleoside + ATP

UMP +ADP

Uridine phosphorylase

Uracil+ 1-phosphoribose

UMP +ADP

Salvage pathway of pyrimidine nucleotides
degradation of pyrimidine nucleotides
Degradation of pyrimidine nucleotides

nucleotide

nucleosides

phosphoribose pyrimidine

Nucleotidase

Nucleoside phosphorylase

slide26

Thymine

β-ureidoisobutyrate

H2O

β-aminoisobutyrare

Excreted

in urine

Succinyl CoA

TAC

Glucose

Cytosine

NH3

Uracil

dihydrouracil

H2O

+

+

CO2 + NH3

β-alanine

liver

Acetyl CoA

Urea

TAC

deoxyribonucleotide biosynthesis

dNDP

NDP

Deoxyribonucleotide biosynthesis

Ribonucleotide reductase

kinase

dNDP+ATP

dNTP + ADP

biosynthesis of ndp and ntp

Kinase

Kinase

ATP

ADP

ATP

ADP

Kinase

Kinase

XMP

XDP

XTP

YTP

YDP

YTP

YDP

Biosynthesis of NDP and NTP

AMP

ADP

ATP

section 10 3

Section 10.3

Dysmetabolism of nucleotides and antimetabolites

dysmetabolism of nucleotides
Dysmetabolism of nucleotides
  • Caused by the genetic defect or regulatory abnormality of some enzymes participating nucleotide metabolism.

Gout:pain and tenderness, redness, warmth, and swelling in some joints

Causes:too much uric acid forms crystals in joints and cause inflammation

antimetabolites
Antimetabolites
  • The analogs of ribonucleotide metabolite intermediates synthesized artificially.
  • Can interfere, inhibit and block the ribonucleotide metabolism.
  • Used as drugs.
slide32

Hypoxanthine

  • Purine ribonucleotide metabolite analogs

6-mercaptopurine(6-MP)

  • Pyrimidine ribonucleotide metaboliteanalogs : 5-fluorouracil(5-FU),

(6-MP)

(T)

(5-FU)

slide33
Amino acid analogs

azaserine(AS)

  • Folic acid analogs

methotrexate(MTX)

  • Nucleoside analogs:

arabinosyl cytosine(ara-c),

cyclo-cytidine(cyclo-c)

  • Metabolite analogs applied to ribonucleotide reductase

hydroxyurea(HU)

slide34

NAD+

AMP

lipid metabolism
Lipid metabolism
  • Lipolysis, β-Oxidation (Ketone Bodies), degradation of glycerophospholipids, cholesterol

key enzymes, main steps, products

  • synthesis of palmitic acid, triacylglycerols, glycerolphospholipids, cholesterol

key enzymes, main steps, material

slide36

Essential Fatty Acids, lipoproteins (classification, function) , HSL

  • Hyperlipoproteinemia, hypercholesterolemia,
  • ketonemia, ketonuria, ketoacidosis
  • reason or mechanism.
protein catabolism
Protein catabolism
  • Nitrogen Balance, Essential Amino Acids , Complementary effect, Putrefaction, Amino acid metabolic pool, Ketogenic amino acids, Ketogenic and glucogenic amino acids.
  • Digestion of dietary proteins, degradation of protein, deamination, decarboxylation

key enzymes, main pathway, main products

  • ALT, AST(function)
slide38

SAM, PAPS, GSH, Dopamine , creatine phosphate (function, formation)

  • Ammonia, One Carbon Units
  • carrier, source, utilization
  • Hyperammonemia, PUK, Albinism
  • damage, mechanism
nucleotide metabolism
Nucleotide metabolism
  • Function of neucleotides
  • de novo synthesis of purine and pyrimidine nucleotides

material, character, main steps,

  • Salvage pathwayof purine and pyrimidine
  • Degradationof purine and pyrimidine nucleotides

products

  • Deoxyribonucleotide biosynthesis
homework
Homework
  • Explain the following concepts:

Essential Amino Acids, Lipolysis

Amino acid metabolic pool

lipoproteins

  • Simple questions:

1. describe the source, transport and metabolic pathway of ammonia.

2. what do you know about ketoacidosis?