THE MINISTRY OF PUBLIC HEALTH OF UKRAINEZAPORIZHIA STATE MEDICAL UNIVERSITY

Nucleotide metabolismits regulation and

disorders

Produced by Ass.professor Krisanova N.V.

ATP use in a cell

ATP

Donor of phosphate in

substrate phosphorylation

Precursor of secondary

messenger cAMP for

hydrophylic hormones

Energy source for

anabolic pathwaysEnergy source for active

transport across

membrane

Energy source for physiological

functions of specialized cells

A substrate for repli-

cation and trascription

The use of other nucleotides in a cell

CTP:• A substrate for Phosphatidyl choline synthesis

• Energy source

•A substrate for transcription and replication

UTP:• A substrate for transcription, glycogenesis and

UDP-glucuronic acid formation

GTP:• Donor of phosphate group (Gluconeogenesis)

• Energy source

• Precursor for cGMP and d-GTP

• A substrate for transcription and replication

DIGESTION OF

DEOXYRIBONUCLEOPROTEIN (DNP)

IN GIT

STOMACH

DUODENUM

SMALL INTESTINE

Denaturation in two parts : DNA and

Proteins; the unwinding of double helix

of DNA; proteins degradation

beginning

Continuation of protein degradation;

DNA degradation up to nucleosides;

Absorption of nucleosides

LARGE

INTESTINEPartial nucleosides transformation (~3%)

up to uric acid, ammonia and carbon

dioxide under the influence of microflora

enzymes

Adenosine

NH

N

N

O

NH2N

O

OHOH

HH

H

CH2

H

HO

N

NN

N

NH2

O

OHOH

HH

H

CH2

H

HO

Guanosine

Uridine

O

HOH

HH

H

CH2

H

HO

N

NH

O

O

H3C

d-Thymidine

N

NH2

ON

O

OHOH

HH

H

CH2

H

HO

Cytidine

HO

NH

O

ON

O

OHOH

HH

HH

N

NN

N

NH2

NH

CHNN

H

N

R

O

NH

NN

N

R

O

NH

NH

NH

HC

N

O

O

NH

NH

NH

HN

O

O

O

NH

NN

N

O

NH2

R

NH

NNH

N

O

NH2

H2O

NH3

H3PO4 R-PO3H2

1/2 O2

H2O

H2O2

H2O

1/2 O2

H2O2

H2O

NH3

H3PO4

R-OPO3H2

Adenosine

Inosine

Hypoxanthine

Xanthine

Uric acid

Guanine

Guanosine

R - the fragment

of ribose

(1)

(2)

(3)(4)

(5)

(6)

NH

NH

(E)

NH

HN

O

O

O

N

NNH

N

OH

OH

HO

Enol-formKeto-form

N

NNH

N

ONa

OH

HO

Na+

Conversion for uric acid and formation

of sodium urate

H+

Sodium Urate

N

N

NH2

O

NH

N

O

O

NH

N

O

O

H3C

RR R

Reductase

NADP+

Hydrolase

+H2O +H2O

N-carbamoylpropionic acid N-carbamoyl-beta-isobutyrate

DEAMINATION

DECARBOXYLATION

Beta-alanine Beta-aminoisobutyrate

CO2 CO2

Cytidine

Uridine Thymidine

Uracil Thymine

Dihydrouracil DihydrothymineNADPH+H

+

NH3

NH3 NH3 UreaUrea

Phosphorylase

Pi Ribose-5P

Synthesis de novo of purine nucleotides

OHCH2OP*

OH

O

OH

Ribose-5-PO-P*-O-P*CH2OP*

OH

O

OH

Phosphoribosyl

pyrophosphate

ATP AMPMg

2+

Synthetase

1)

2)PRPP + c (CH2)2 CH

NH2

COOH

NH2

O

NH2CH2OP*

OH

O

OH

Glu

H2OPhosphoribosyl aminotransferase

3)

NH2CH2OP*

OH

O

OH

+

NH2

CH2

COOH

Glutamine

Glycine

NHCH2OP*

OH

O

OH

CO

CH2

NH2

Glycinamide-ribosyl-5-P

ATP ADPH3PO4

Mg2+

Glycine amide-ribosyl-5-P

synthetase

PRPP

H4P2O7

(PRPP)

Phosphorybosylamine

NH

NN

N

O

O

OHOH

HH

H

CH2

H

OPHO

OH

O

1

2

3

4

567

8

9

Gln

GlyAsp

CO2

Formyl-THFA

Methenyl-THFA

PRPP

Gly - Glycine

Asp - Aspartic acid

THFA - Tetrahydrofolic acid

Gln - Glutamine

Synthesis of Inosine monophosphate (IMP)

Second phase of purine nucleotide synthesis

IMP

Adenosyl succinate

Xanthosine monophosphate

AMP GMP

Asp

GTPGDP

H3PO4

Mg2+

NADNADH+H

+

ATP

ADPH3PO4

Gln

Glu

Adenosyl succinate lyase;Adenosyl succinate synthetase;

GMP-synthetase

IMP-dehydrogenase

(1) (2)

(3) (4)Fumarate

1 -- 2 --3 -- 4 --

Salvage reactions found in neurons and RBC

Hypoxanthine IMPHypoxanthine guanine phosphoribo-

syl pyrophosphate transferase (HGPRPPT)

Guanine

PRPP

AMPAdenine

PRPP

PRPP

GMP

Adenine phosphoribosyl pyro-

phosphate transferase

H4P2O7

H4P2O7

H4P2O7

HGPRPPT

Synthesis de novo of UMP

HAD+

PRPP

Orotate phospho-

ribosyl transferaseOrotidyl decar-

boxylase

CO2

H2N C

O

P

+

H2N

CH

CH2

COOH

COOH

HN

CH

CH2

COOH

HOOC

CO NH2

***Aspartate transcarbamoylase

H3PO4

Dihydro

orotase

H2O

Dihydro

orotic

acid

Orotic

acid

Carbamoyl

phosphate

Aspartate

Carbamoyl

aspartic acid

H4P2O7

NH

NH

O

OHOOC

NH

NH

O

OHOOC

NH

N

O

O

NH

N

O

O

RHOOC

R

HADH+H+

***

UMP

R - ribose-5- phosphate residue

UMP UDP UTPkinasekinase

UTP Gln ATP CTP ADP H3PO4 Glu++ + ++Synthetase

(1)

(2)

ATP ADP ATP ADP

Methylene-THFA

UDP dUDP dUMP dTMPPhosphatase

Thioredoxin

ReducedThioredoxin

oxidized

NADP+NADPH+H

+**

* - Ribonucleoside diphosphate

reductase

** - Thioredoxin reductase

* ***

*** - Deoxythymidilate synthetase

Dihydrofolate

H3PO4

Synthesis of UDP, UTP, CTP, dTMP

Riboso-5- P+ATP

PRPP

5-phosphoribosylamine

-

-

-

+ +

1

2

. . .

IMPAdenylosuccinate

Xanthosine

monophosphate

AMP

ADP

ATP

GMP

GDP

GTP

ATP + CO2+ Gln

Carbamoyl-

phosphate

Carbamoyl

aspartate

***

UDPCTP

dUDPdUMPdTMPTDPUTP

(-)

UMP

(-)

(+)

The regulation of nucleotide synthesis

• Special vitamins intake: B9, B12, B3

(PP). B12 is required for formation of

some folic acid derivatives.

•Energy requirement: per 1 mole of

synthesized AMP or GMP - 5 ATP; per

1 mole of UMP – 2 ATP

The main information

about synthesis of nucleotides

•The location of reactions in a cell:

cytoplasma, EPR, nucleoplasma

In the blood plasma:

[ URATES] < 0.42 mmole/L (for men)

[ URATES] < 0.3 mmole/L (for women)

The values which are higher provide the

state named Hyperuricemia

Disorders of nucleotide metabolism

The GOUT development is in 15% of patients from

all having Hyperuricemia

Factors, which can cause the gout in patients

with hyperuricemia:

•Overcooling of human organism

•The sharp change of patient`s diet

Inherited disorders

of nucleotide metabolism

PRPP synthetase may be with abnormal

features:

•Superactive (increased Vmax) → purine

overproduction → gout

•Resistance to feedback inhibition →

purine overproduction → gout

•Low Km for ribose-5-P→ purine

overproduction → gout

Inherited disorders

of nucleotide metabolism

Hypoxanthine guanine phosphoribosyl

pyrophosphate transferase (HGPRT)

•Partial deficiency → purine overpro-

duction → gout

•Complete deficiency (Lesch-Nyhan syn-

drome) → purine overproduction, the

main clinical symptoms: self-mutilation,

mental retardation, usually death in early

childhood.

Secondary reason for the

development of hyperuricemia

The complete lack or deficiency of glucose-6-

phosphatase

High levels of glucose involved in HMP shunt

Excess levels of ribose-5-phosphate

Stimulation of PRPP synthetase

22

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