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Lecture 42 - 51 > Purine Metabolism > Flashcards

Purine Metabolism Flashcards

1
Q

Are nucleotides synthesized in the oxy or deoxy form?

A

oxy

if cell needs DNA synthesis, then oxy is converted to deoxy

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2
Q

Purine Nomenlature

A

example: adenine

adenine -> adenosine -> adenosine monophosphate

purine nucleosides end in “osine”

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3
Q

Why are drugs/antiviral analogues administered as nucleosides?

A

They can pass the plasma membrane. Once phosphorylated (nucleotide) have a negative charge and cannot.

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4
Q

What are the active form of nucleotides?

A

di and tri phosphates

nucleoside monophosphates can be converted to di/triphosphates via nucleoside monophosphate kinase (turn mono=>diphosphate)

AND

nucleoside diphosphate kinase (turn di=>triphosphate)

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5
Q

What is the purine proteome?

A

purine binding proteins comprise a family of 3-4,000 proteins (27-30,000 genes). 10% of proteins in body and 50% of druggable targets in biology.

Ex: kinases, helicases, reductases, transferases etc.

kinase inhibitor in leukemia- imatinib- 95% remission rate

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6
Q

What are the common purine bases?

A

Adenine 6-aminopurine

Guanine 2-amino, 6-oxy

Hypoxanthine 6-oxy

Xanthine 2,6-dioxy

nitrogen for all these inside ring are 1,3,7,9 positions.

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7
Q

what is a competitive inhibitor of adenosine?

A

caffiene

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8
Q

What are two pathways to make purines and pyrimidines?

A

de novo biosynthetic pathways: from non base molecules

salvage pathways: reutilization of bases from dietary or catabolic sources

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9
Q

In de novo synthesis of purines A & G, how is ribose-5-phosphate activated?

A

step 1: Ribose-5-phosphate (PRPP synthase + ATP) => PRPP + ATP

PRPP= 5-phosphoribosyl-1-pyrophosphate; inhibited by AMP, GMP, IMP

step 2: PRPP (amidophosphoribosyl transferase + glutamine) => 5-phosphoribosylamine + PPI+(glutamate)

rate limiting step* inhibited by AMP, GMP, IMP

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10
Q

Where do the atoms of IMP come from?

A

inosine monophosphate

glycine, 10 formyl THF, amide of glutamine, aspartate, CO2

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11
Q

What is the precursor for AMP and GMP?

A

IMP

inosine monophospate

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12
Q

How is AMP synthesized from IMP?

A

step 1: IMP (adenylosuccinate synthetase + aspartic acid + GTP) => adenylosuccinate

step 2: (adenylosuccinase) => AMP + fumarase

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13
Q

How is GMP synthesized from IMP?

A

IMP (IMP dehydrogenase + H2O + NAD) => xanthosine monophosphate

(GMP synthetase + Glutamine + ATP) => GMP + glutamate

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14
Q

How are AMP and GMP maintained at balanced stoichiometric levels?

A

When AMP is made, GTP is required. Therefore, is not enough GTP, you cannot make AMP.

When GMP is made, ATP is required…

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15
Q

What are the nitrogen sources for Adenine and Guanine?

A

hypoxanthine-IMP + ASPARTATE (N source) forms adenine

xanthine-XMP + GLUTAMINE (N source) forms guanine

common mechanism is conversion of carbonyl oxygen to amino group in A & G synthesis

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16
Q

What inhibits the synthesis of AMP and GMP?

A

Themselves (final product AMP and GMP respectively)

17
Q

What is the mechanism behind the salvage pathway?

A

just one step to make A and G from old bases

PRPP + Adenine (APRT)=> adenylate/AMP

APRT- adenine phosphoribosyl transferase

PRPP + Guanine (HGPRT)=> guanylate/AMP

HGPRT- hypoxanthine guanine phosphoribyl transferase

18
Q

What are the stages of nucleotide metabolism?

A

Nucleic acids can be broken down to endonucleotides and then to nucleoside monophosphates which can be converted back to nucleosides and nucleic acid synthesis

19
Q

how are monophosphate nucleosides broken down?

A

First, nucleotidase cleaves and removes the phosphate

requires: H2O and ATP; A Pi is released

form nucleoside

Then, phosphorylase cleaves the glycosidic linkage

Pi from first reaction combines with free ribose=> ribose-1-phosphate

free nucleobases can either be degraded to uric acid OR enter the salvage pathway where PRPP is added back onto bases to form their respective nucleoside triphosphate

20
Q

How are purines degraded to urate?

A

GMP undergoes cleavage by nucleotidase followed by phosphorylase:

GMP -> Guanosine -> GUANINE loses NH4+ -> Xanthine

*Note Adenine => IMP via adenosine deaminase (ADA)

AMP (adenylate deaminase)-> IMP (nucleotidase) -> inosine (phosphorylase) -> hypoxanthine (xanthine oxidase) -> Xanthine

Xanthine (xanthine oxidase) => Urate

*xanthine oxidase requires H2O and O2; hydrogen peroxide is a byproduct

*deaminase: removal of NH4+

21
Q

What happens to Uric Acid? What happens if there is a build up of Uric Acid?

A

normally, most of it gets excreted in the urine.

If too much: Hyperuricemia: urate is not soluble in plasma or tissues. Precipitates as crystals which bind and activate macrophages. Cytokines produced -> sterile inflammation

22
Q

What are two causes of hyperuricemia?

A

decreased excretion of urate: 80% gout cases

related to idiopathic, renal disease, diabetes insipidus, hypertension, down syndrome etc.

increased productino of urate: 20% gout cases

due to PRPP synthase overactivity, hemolytic diseases

also- HGPRT deficiency - Less Nychan disease which is exaccerbated by alcoholism

23
Q

What happens when you are HGPRT deficient?

A

lose salvage pathway!

build up of PRPP and this pushes against inhibition by IMP AMP GMP

Therefore, shift more towards synthesis pathway

initial increase in synthesis- then increase degradation

*HGPRT has polymorphisms in general population allowing people to have different levels of it

24
Q

What is the treatment for gout?

A

Allopurinol- “suicide inhibitor” for xanthine oxidase

similar structure to xanthine but N moved from 7 to 8 position

xanthine oxidase binds allopurinol- cannot form uric acid

25
Q

What happens when you are VERY HGPRT deficient?

A

Lesch-Nyhan Syndrome

X-linked recessive

practically have no HGPRT, decreased IMP GMP, increased PRPP

severe hyperuremia: gouty arthritis, kidney stones, tophi (deposits)

neurological impairment: spasticity, overactive reflex

behavioral problems: cognitive dysfunction, agression, self-harm

26
Q

What is SCID?

A

Severe Combined Immunideficiency Syndrome

Autosomal Recessive

due to deficiency in ADA (adenine -> IMP)

large buildup of deoxyATP toxic because they inhibit ribonucleotide reductase. They are especially toxic to T and B cells which die off=> decreased immune response

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Lecture 42 - 51 (7 decks)

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