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Nucleic Acid metabolism Nucleic Acid metabolism

Nucleic Acid metabolism - PowerPoint Presentation

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Nucleic Acid metabolism - PPT Presentation

De Novo Synthesis of Purine Nucleotides We use for purine nucleotides the entire glycine molecule atoms 4 57 the amino nitrogen of aspartate atom 1 amide nitrogen of glutamine atoms 3 9 components of the ID: 601104

acid synthesis purine urate synthesis acid urate purine enzyme uric xanthine pyrimidine prpp free phosphate nucleotides ring nucleotide group

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Slide1

Nucleic Acid metabolismSlide2

De Novo

Synthesis of

Purine

Nucleotides

We use for

purine

nucleotides the entire

glycine

molecule (atoms 4, 5,7), the amino nitrogen of

aspartate

(atom 1), amide nitrogen of glutamine (atoms 3, 9), components of the

folate

-one-carbon pool(atoms 2, 8), carbon dioxide, ribose 5-P from glucose and a great deal of energy in the form of ATP. In de novo synthesis, IMP is the first nucleotide formed. It is then converted to either AMP or GMP.Slide3

PRPP

Since the

purines

are synthesized as the

ribonucleotides

, (not as the free bases) a necessary prerequisite is the synthesis of the activated form of ribose 5-phosphate. Ribose 5-phosphate reacts with ATP to form

5-Phosphoribosyl-1-pyrophosphate (PRPP)

.Slide4

This reaction occurs in many tissues because PRPP has a number of roles -

purine

and

pyrimidine

nucleotide synthesis, salvage pathways, NAD and NADP formation. The enzyme is heavily controlled by a variety of compounds (

di

- and tri-phosphates, 2,3-DPG), presumably to try to match the synthesis of PRPP to a need for the products in which it ultimately appearsSlide5

Commitment Step

De novo

purine

nucleotide synthesis occurs actively in the

cytosol

of the liver where all of the necessary enzymes are present as a macro-molecular aggregate. The first step is a replacement of the pyrophosphate of PRPP by the amide group of glutamine. The product of this reaction is

5-Phosphoribosylamine

. The amine group that has been placed on carbon 1 of the sugar becomes nitrogen 9 of the ultimate

purine

ring. This is the commitment and rate-limiting step of the pathwaySlide6

Control of

De Novo

Synthesis

Control of

purine

nucleotide synthesis has two phases. Control of the

synthesis as a whole

occurs at the

amidotransferase

step by nucleotide inhibition and/or [PRPP]. The second phase of control is involved with

maintaining an appropriate balance (not equality) between ATP and GTP

. Each one stimulates the synthesis of the other by providing the energy. Feedback inhibition also controls the branched portion as GMP inhibits the conversion of IMP to XMP and AMP inhibits the conversion of IMP to

adenylosuccinate

.Slide7

De Novo

Synthesis of

Pyrimidine

Nucleotides

Since

pyrimidine

molecules are simpler than

purines

, so is their synthesis simpler but is still from readily available components. Glutamine's amide nitrogen and carbon dioxide provide atoms 2 and 3 or the

pyrimidine

ring. They do so, however, after first being converted to

carbamoyl

phosphate. The other four atoms of the ring are supplied by

aspartate

. As is true with

purine

nucleotides, the sugar phosphate portion of the molecule is supplied by PRPP.

Carbamoyl

Phosphate

Pyrimidine

synthesis begins with

carbamoyl

phosphate

synthesized in the

cytosol

of those tissues capable of making

pyrimidines

(highest in spleen, thymus,

GItract

and testes). This uses a different enzyme than the one involved in urea synthesis.

Carbamoyl

phosphate

synthetase

II (CPS II)

prefers glutamine to free ammonia and has no requirement for N-

AcetylglutamateSlide8

Formation of

Orotic

Acid

Carbamoyl

phosphate condenses with

aspartate

in the presence of

aspartate

transcarbamylase

to yield N-

carbamylaspartate

which is then converted to

dihydroorotate

.

In man,

CPSII, asp-

transcarbamylase

, and

dihydroorotase

activities

are part of a

multifunctional protein

.

Oxidation of the ring by a complex, poorly understood enzyme produces the free

pyrimidine

,

orotic

acid. This enzyme is located on the outer face of the inner mitochondrial membrane, in contrast to the other enzymes which are

cytosolic

. Note the contrast with

purine

synthesis in which a nucleotide is formed first while

pyrimidines

are first synthesized as the

free base

. Slide9

Salvaging

Purines

As a salvage process though, we are dealing with

purines

. There are two enzymes, A-PRT and HG-PRT.

A-PRT

is not very important because we generate very little adenine. (Remember that the catabolism of adenine nucleotides and nucleosides is through

inosine

).

HG-PRT

, though, is exceptionally important and it is inhibited by both IMP and GMP. This enzyme salvages guanine directly and adenine indirectly. Remember that AMP is generated primarily from IMP, not from free adenineSlide10

Lesch-Nyhan

Syndrome

HG-PRT is deficient in the disease called

Lesch-Nyhan

Syndrome

, a severe neurological disorder whose most blatant clinical manifestation is an uncontrollable self-mutilation.

Lesch-Nyhan

patients have very

high blood uric acid

levels because of an essentially

uncontrolled

de novo

synthesis

. (It can be as much as 20 times the normal rate). There is a significant increase in PRPP levels in various cells and an inability to maintain levels of IMP and GMP via salvage pathways. Both of these factors could lead to an increase in the activity of the

amidotransferase

.Slide11

Purine

Catabolism

The end product of

purine

catabolism in man is

uric acid

. Other mammals have the enzyme

urate

oxidase

and excrete the more soluble

allantoin

as the end product. Man does not have this enzyme so

urate

is the end product for us. Uric acid is formed primarily in the liver and excreted by the kidney into the urine

.Slide12

Bases to Uric Acid

Both adenine and guanine nucleotides converge at the common intermediate

xanthine

. Hypoxanthine, representing the original adenine, is oxidized to

xanthine

by the enzyme

xanthine

oxidase

. Guanine is

deaminated

, with the amino group released as ammonia, to

xanthine

. If this process is occurring in tissues other than liver, most of the ammonia will be transported to the liver as glutamine for ultimate excretion as urea.

Xanthine

, like hypoxanthine, is oxidized by oxygen and

xanthine

oxidase

with the production of hydrogen peroxide. In man, the

urate

is excreted and the hydrogen peroxide is degraded by

catalase

.

Xanthine

oxidase

is present in significant concentration only in liver and intestine. The pathway to the nucleosides, possibly to the free bases, is present in many tissues.Slide13

Gouts and

Hyperuricemia

Both

undissociated

uric acid and the monosodium salt (primary form in blood) are only sparingly soluble. The limited solubility is not ordinarily a problem in urine unless the urine is very acid or has high [Ca

2+

]. [

Urate

salts

coprecipitate

with calcium salts and can form stones in kidney or bladder.] A very high concentration of

urate

in the blood leads to a fairly common group of diseases referred to as gout. The incidence of gout in this country is about 3/1000.

Gout

is a group of pathological conditions associated with markedly elevated levels of

urate

in the blood (3-7 mg/dl normal).

Hyperuricemia

is not always symptomatic, but, in certain individuals, something triggers the deposition of sodium

urate

crystals in joints and tissues. In addition to the extreme pain accompanying acute attacks, repeated attacks lead to destruction of tissues and severe arthritic-like malformations. The term gout should be restricted to

hyperuricemia

with the presence of these

tophaceous

deposits.Slide14

Urate

in the blood could accumulate either through an overproduction and/or an

underexcretion

of uric acid. In gouts caused by an

overproduction

of uric acid, the defects are in the control mechanisms governing the production of - not uric acid itself - but of the nucleotide precursors. The

only major control of

urate

production that we know so far is the availability of substrates (nucleotides, nucleosides or free bases)

.

One approach to the treatment of gout is the drug

allopurinol

, an isomer of hypoxanthine.

Allopurinol

is a substrate for

xanthine

oxidase

, but the product binds so tightly that the enzyme is now unable to oxidized its normal substrate. Uric acid production is diminished and

xanthine

and hypoxanthine levels in the blood rise. These are more soluble than

urate

and are less likely to deposit as crystals in the joints. Another approach is to stimulate the secretion of

urate

in the urine.Slide15

Pyrimidine

Catabolism

In contrast to

purines

,

pyrimidines

undergo ring cleavage and the usual end products of catabolism are beta-amino acids plus ammonia and carbon dioxide.

Pyrimidines

from nucleic acids or the energy pool are acted upon by

nucleotidases

and

pyrimidine

nucleoside

phosphorylase

to yield the free bases. The 4-amino group of both cytosine and 5-methyl cytosine is released as ammonia.

Ring Cleavage

In order for the rings to be cleaved, they must first be

reduced by NADPH

. Atoms 2 and 3 of both rings are released as ammonia and carbon dioxide. The rest of the ring is left as a

beta-amino acid

. Beta-amino

isobutyrate

from thymine or 5-methyl cytosine is largely excreted. Beta-

alanine

from cytosine or

uracil

may either be excreted or incorporated into the brain and muscle

dipeptides

,

carnosine

(his-beta-ala) or

anserine

(methyl his-beta-ala).Slide16
Slide17