Nucleotide metabolism

Chapter 10

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

Nucleotide Synthesis and Degradation

Digestion and absorption of nucleotide

Nucleoprotein

Protein Nucleic acid

NucleasesNucleotide

Nucleotidase

Phosphate NucleosideNucleosidase

Base Ribose

Absorption Blood

Metabolism of Purine nucleotides Biosynthesis of purine nucleotides

de novo synthesis 从头合成 salvage pathway 补救合成

GMPAMP

1.De novo synthesis of purine nucleotides

CO2 Glycine

One carbon

unitOne carbon

unit

Glutamine

Aspartate

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

R-5-P（ 5’-phosphoribose ）

ATPAMP

PRPPK

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

AMP

GMP

H2N-1-R-5´-P（ 5´-phosphoribosyl-amine ）

Gln

GluGlutamine PRPP amidotransferase

(GPRT)

PP-1-R-5-P （ 5’-phosph

oribose 1’-pyrophosphate, PRPP ）

磷酸核糖焦磷酸

Regulation of de novo synthesis of purine nucleotides

PRPPKPRPP

GPATPRA IMP

Adenyl-succinate

AMP ADP ATP

XMP GMP GDP GTP

++

_ _ _

__

IMP

Adenyl-succinate

XMP

AMP ADP ATP

GMP GDP GTPATP

GTP

_

_

++

R-5-P

ATP

2. Salvage synthesis of purine nucleotides

Material:

PRPP, purine (conjunction)

nucleosides (phosphorylation)

Location:

brain and bone marrow

or

adenine+ PRPP AMP + PPiAPRT

hypoxanthine+PRPP IMP + PPiHGPRT

guanine+ PRPP HGPRT GMP + PPi

adenosineAdenylate kinase

ATP ADPAMP

APRT: adenine phosphoribosyltransferase

HGPRT: hypoxanthine-guanine

phosphoribosyltransferase

Degradation of purine nucleotides

nucleotide

nucleosides

ribose-1-phosphate purine

salvage pathway uric acid

Nucleotidase

Nucleoside phosphorylase

尿酸

IMP

Neucleo-tidase

Excretion

Metabolism of pyrimidine nucleotides Biosynthesis of pyrimidine nucleotides

de novo synthesis

salvage pathway

1.De novo synthesis of pyrimidine nucleotides

Aspartate

Glutamine

CO21

54

3

62

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 1. formation of Carbamoyl phsphate (CP)

CO2 + glutamine + H2O + 2ATP

C

O

H2N O ~ PO32- + 2ADP + Pi

carbamoyl phosphate

Carbamoyl phosphate synt

hase (CPS )Ⅱ Ⅱ

CPS-I CPS-II

肝细胞线粒体中

氨

N-乙酰谷氨酸

胞液（所有细胞）

谷氨酰胺

无

分布

氮源

变构激活剂

功能 尿素合成 嘧啶合成

CPS-I CPS-II

肝细胞线粒体中

氨

N-乙酰谷氨酸

胞液（所有细胞）

谷氨酰胺

无

分布

氮源

变构激活剂

功能 尿素合成 嘧啶合成

氨基甲酰磷酸合成酶 I、II 的区别The different between Carbamoyl phosphate synthaseⅠ,Ⅱ

Location

Source of nitrogen

Activator Function

NH3 Glutamine

NoneN-acetylglutamate

Mitochondria of liver cells

cytosol of all cells

Formation of urea Formation of pyrimidine

C

O

H2N O ~ PO32-

carbamoyl phosphate

+Aspartate

Carbamoyl aspartate

PRPPOrotate 乳清酸

UMP

2. Formation of UMP

ATP ADP

UMPKUDP

NDK

ATP ADP

UTP

CTP synthase

GlnATP

GluADP

3. Synthesis of CTP, dTMP or TMP

dCMPdUDP

dUMP

dTMP

TMP synthase

Regulation of de novo synthesis of pyrimidine nucleotides

ATP + CO2+ glutamine

Carbamoyl phosphate

UMP

Carbamoyl aspartate

UTP CTP

aspartate

ATP + 5-phosphate ribosePRPP

Pyrimidine nucleotides-

+

-

-

-Purine nucleotides-+

1.Activated by substrates

2. Inhibited by products

Salvage pathway of pyrimidine nucleotides

Uracil + PRPP UMP + PPi

Uracil phosphate ribosyltransferase

Uridine + ATPUridine kinase

UMP +ADP

Uracil + 1-phosphoribose Uridine + Pi

Uridine phosphorylase

nucleotide

nucleosides

phosphoribose pyrimidine

Degradation of pyrimidine nucleotides

Nucleotidase

Nucleoside phosphorylase

Cytosine

NH3

Uracil

dihydrouracil H2O

CO2 + NH3

β-alanine

Thymine

β-ureidoisobutyrate

H2O

Acetyl CoA

TAC

liver

Urea

+ +

β-aminoisobutyrate

Succinyl CoA

TAC Glucose

Excreted in urine

Deoxyribonucleotide biosynthesis

NDP dNDP

Ribonucleotide reductase

dNDP + ATP kinase

dNTP + ADP

Biosynthesis of NDP and NTP

AMP ADP ATP

ADPATP

Kinase

ADPATP

Kinase

XMP XDP XTP

YDPYTP

Kinase

YDPYTP

Kinase

Section 10.3

Dysmetabolism of nucleotides and antimetabolites

Dysmetabolism of nucleotides

Caused by the genetic defect or regulatory abnormality of some enzymes participating nucleotide metabolism.

Gout （痛风）： pain and tenderness, redness, heat, swelling and joint inflammation

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

Risk Factors Obesity/being overweight more common in men than women Certain medicines Certain foods and alcoholic beverages Genetics Enzyme defect

Medication

xanthine-oxidase inhibitors, 黄嘌呤氧化酶抑制剂

allopurinol 别嘌呤醇uricosurics, 促尿酸尿剂 urate oxidases 尿酸氧化酶

Limit your consumption of certain types of meat ： beef, pork, lamb, and “organ meats” (such as liver, kidney, and brain), as well as meat extracts and gravies.

Reduce or eliminate alcohol consumption, especially beer.

Reduce your use of oatmeal, dried beans, spinach, asparagus, cauliflower, and mushrooms

High consumption of seafood is associated with an increased risk of gout.

Antimetabolites

The analogs of ribonucleotide metabolite intermediates synthesized artificially.

Can interfere, inhibit and block the ribonucleotide metabolism.

Used as drugs.

Purine ribonucleotide metabolite analogs

6-mercaptopurine(6-MP)

Hypoxanthine (6-MP)

Pyrimidine ribonucleotide metabolite analogs :

5-fluorouracil(5-FU),

(T) (5-FU)

NAD+

AMP

Biological oxidation Respiratory Chain and its composition ，

How many Respiratory Chain in the mitochondria? What is the sequence of them?

Oxidation Phosphorylation and the mechanism of it

the regulation of it (Cyanide)? P/O ratio How many ATP produced by Respiratory

Chain? How to use cytosolic NADH ? energy-rich compounts

Protein catabolism

Nitrogen Balance, Essential Amino Acids , Complementary effect, Putrefaction, Amino acid metabolic pool, Ketogenic amino acids, Ketogenic and glucogenic amino acids. deamination, decarboxylation key enzymes, main pathway, main products

ALT, AST (function) SAM, PAPS, GSH, Dopamine , creatine ph

osphate (function, formation) Ammonia, One Carbon Units

carrier, source, utilization Hyperammonemia, PKU, Albinism

damage, mechanism

Nucleotide metabolism Function of neucleotides de novo synthesis of purine and pyrimidine

nucleotides

material, character, main steps, Salvage pathway of purine and pyrimidine Degradation of purine and pyrimidine nucle

otides

products ， Gout Deoxyribonucleotide biosynthesis