NUCLEOTIDE METABOLISM(2)

Dr.Samah Badr

Msc.MBBS

OBJECTIVES:

• Introduction

• Synthesis of pyrimidine nucleotides.

• Degradation of pyrimidine nucleotides

• Regulation of pyrimidine nucleotides metabolism

• Disorders of pyrimidine metabolism.

DR.SAMAH BADR

INTRODUCTION:

• An aromatic nitrogen bases -containing,

a single six membered ring.

• 3 bases: cytosine(C),uracil(U) and thymine (T)

In DNA (C) & (T).

In RNA (C) & (U).

DR.SAMAH BADR

CONT…

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SYNTHESIS OF PYRIMDINENUCLEOTIDES

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SITE OF SYNTHESIS:

✓ Much simpler pathway compared to purine metabolism.

✓ Tissues:

• The major site is : liver.

✓ Subcellular site:

• Cytosol and Mitochondria.

• All reactions occur in the cytosol.

• The formation of orotate from dihydroorotate occurs in mitochondriand all other reactions occur in the cytosol

✓ There are two pathways for the synthesis of pyrimidines nucleotides:

DR.SAMAH BADR

DE NOVO

SYNTHESIS:

Formation of pyrimidine

nucleotides from pyrimidine

bases)

Salvage

pathway

The formation of pyrimidine ring

structure followed by the addition of

ribose phosphate.

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SOURCE OF PYRIMIDINE ATOMS:

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CPS I AND CPS II ENZYMES:

CPS I CPS II

•SITE Mitochondria Cytoplasm

•Pathway Urea Pyrimidine

•Source for (N) Ammonia Glutamine

•Inhibitor -------- CTP

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PHOSPHORYLATION:(UMP UTP & CTP)

• Nucleoside monophosphate kinase catalyses' transfer of Pi to UMP

to form UDP.

• Nucleoside diphosphate kinase catalyses' transfer of Pi from ATP to

UDP to form UTP.

• CTP formed from UTP via CTP Synthetase driven by ATP

hydrolysis.

• Glutamine provides amide nitrogen for C4 in animals.

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DR.SAMAH BADR

DEOXY PYRIMIDINE NUCLEOTIDES:

• Ribonucleotide reductase

converts UDP to dUDP.

• De-oxyuridine diphosphate

(dUDP) is dephosphorylated to

dUMP which acts as a

substrate for thymidine

monophosphate (TMP).

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METHYLATION OF DEOXY-UMP:

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Salvage pathway

SALVAGE PATHWAY:

✓Refers to the formation of pyrimidine nucleotides from pyrimidine

bases.

✓ Significance:

provide a pathway for the utilization of pyrimidine bases derived

from diet(exogenous) and normal turnover of nucleic acids.

DR.SAMAH BADR

CONT…

✓ Two enzymes that catalyze

the reactions of salvage

pathway. They are:

• Uracil phosphoribosyl

transferase (UPRT).

• Thymidine kinase(T.kinase)

✓ PRPP is the source of ribose

5-phosphate.

Uracil + PRPP UPRT UMP + PPi

Thymidine + ATP T.Kinase TMP+ADP

DR.SAMAH BADR

REGULATION OF PYRIMIDINE SYNTHESIS:

• The first two enzymes carbamoyl

phosphate synthase-II and aspartate

transcarbamoylase are allosteric

enzymes .

• CPS II, reaction -1 is feed- back

inhibited by UTP and activated by

PRPP.

• Aspartate transcarbamoylase, reaction-

2, is feedback inhibited by CTP and

activated by ATP.

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DEGRADATION OF PYRIMIDINE NUCLEOTIDES

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DEGRADATION STEPS:

• The pyrimidine nucleotides undergo similar

reactions:

dephosphorylation, deamination and cleavage

of glycosidic bond like that of purine

nucleotides to liberate the nitrogenous

bases(C, U & T).

• The bases are then degraded to highlyl

soluble products β-alanine and β-

aminoisobutyrate.

• These are the amino acid which undergo

transamination and other reactions to finally

produce acetyl CoA and succinyl CoA for

fatty acid synthesis.

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DISORDERS OF PYRIMIDINE METABOLISM

• Disorders of pyrimidine metabolism includes:

✓Orotic aciduria

✓Reye’s syndrome

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OROTIC ACIDURIA:

✓ Is a rare inherited and metabolic disorder characterized by :

• excretion of orotic acid in urine

• severe anemia

• retarded growth(mental and physical)

✓ It is due to the deficiency of the enzymes orotate phosphoribosyl transferase

and OMP decarboxylase of pyrimidine synthesis.

✓ Both these enzymes activities are present on a single protein as bifunctional

enzyme

DR.SAMAH BADR

TREATMENT:

✓effective t/t of orotic aciduria feeding diet rich in uridine or

cytidine

✓These compounds provide pyrimidine nucleotides required for

DNA and RNA synthesis and stop orotic acid synthesis

✓ Allopurinol can precipitate the condition , HOW ??????

DR.SAMAH BADR

Reye’s syndrome:

REYE’S SYNDROME:

✓ This is considered as a secondary orotic aciduria.

✓ Due to defect in ornithine trascarbamoylase ( in urea cycle )

causes the accumulation of carbamoyl phosphate.

✓ This is then diverted for the increased synthesis and excretion

of orotic acid.

DR.SAMAH BADR

THANK YOU