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Dems Unit 02 - 02 > Conversion of AA 21 Nucleotide synth 22 > Flashcards

Conversion of AA 21 Nucleotide synth 22 Flashcards

1
Q

Porphyrins

Heme

A

cyclic compounds that readily bind metal ions

  • usually Fe2+ or Fe3+
  • formed by linkage of 4 pyrrole rings

Heme is one Fe2+ (ferrous) ion corrdinated in center of ring of protoporphyrin IX

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2
Q

The major site of heme biosynthesis is in the ____ and ____.

A

liver, erythrocyte producing cells of bone marrow

bone marrow active in Hb synthesis

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3
Q

The formation of ALA (d-aminolevulinic acid)

  • requires what as a coenzyme
  • why is this step imp
A

All Cs and Ns of the porphyrin molecule are provided by glycine(AA) and succinyl coA (TCA) via ALA synthase (ALAS)

Requires PLP as a coenzyme

1st step of Heme biosynthesis

Rate committed and RLS in porphyrin biosynthesis

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4
Q

Administration of drugs (increases/decreases) ALA synthase activity?

A

increase significantly
Drugs metabolized by P450 system
- (a hemeprotein oxidase system found in liver)

  1. In response to drugs, the synthesis of cytochrome P450 proteins ↑
  2. Enhanced consumption of heme
  3. Causes decrease in the [ heme ] in liver cells
  4. Lower intracellular [ heme ] → increase in ALAS1 → ALA synthesis
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5
Q

Why is ALA elevated and anemia seen in lead poisoning?

A

Condensation of two molecules of ALA → porphobilinogen is extremely sensitive to inhibition by heavy metal ions

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6
Q

Last 2 steps of heme synthesis

A

Copro-porphyrin-ogen III → Proto-porphyrin IX
Fe2+ (ferrous) ion binds spontaneously, but enhanced by ferrochelatase

Proto-porphyrin IX → Heme

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7
Q

Porphyrias

  • common feature
  • most common one (describe)
A

common feature: ↓ synthesis of heme
Accumulation of ALAS1 and toxic intermediates to compensate

Most common porphyria: Porphyria Cutanea Tardia

  • deficiency in uroporphyrinogen decarboxylase (cant convert Uro-porphyrinogen III→ Co-proporphyrinogen III)
  • patients are photosensitive
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8
Q

Degradation of heme → yellow urobilin + brown stercobilin

A
  1. Senescent (120 day old) RBCs are taken up and HEME is broken down to BILIRUBIN by macrophages of reticuloendothelial system (tissue macrophages, spleen, liver)
  2. BILIRUBIN binds to albumin and gets transported to liver, where it dissociates and enters hepatocytes
  3. BILIRUBIN is conjugated with glucuronic acid → BILIRUBIN DIGLUCORONIDE (more soluble)
  4. It is then transported into bile then intestine
  5. Intestinal bacteria removes glucuronic acid → UROBILINOGEN
  6. It can then go to the kidney → yellow urobilin (yellow pee)
    Or it can stay in intestine → brown stercobilin

*this is why high levels of unconjugated bili is bad

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9
Q

PRPP

  • what is it
  • what does it do?
  • how is it made
  • Does Pi and purine ribonucleotides activate or inactivate it?
A

an “activate pentose” that participates in the synthesis and salvage of purines and pyrimidines.

PRPP is made from ATP and Ribose 5 P (HMPP)

Pi activates PRPP synthesis
Purine ribonucleotide inhibits

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10
Q

Committed step of purine nucleotide biosynthesis
- Which on activates and inhibits this step:
AMP, GMP, PRPP

A

Synthesis of 5’-phosphoribosylamine from PRPP + glutamine
(amide group of glutamine replaces pyrophosphate group of PRPP)

Activator: PRPP
Inhibitor: AMP, GMP (end products in pathway)

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11
Q

Nucleotide biosynthesis of IMP

A

the “parent” purine nucleotide

PRPP +4 ATP→ → → IMP

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12
Q

Folic acid analogs and what do they do

A

Methotrexate
inhibit the reduction of dihydrofolate to tetrahydrofolate
(competitive inhibitor to hihydrofolate reductase)
- they limit the amt of THF available for use in purine synthesis and slow down DNA replication in mammal cells.
- Useful in treating rapidly growing cancers!

  • INTERFERES WITH PURINE SYNTHESIS
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13
Q

PABA anologs and what they do

  • what does it require as a coenzyme?
  • do they interfere with purine synthesis?
A

Sulfonamides
Competitively inhibit bacterial synthesis of folic acid.
Purine synthesis requires THF as coenzyme, and sulfa drugs slow it down.

  • DO NOT INTERFERE WITH HUMAN PURINE SYNTHESIS
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14
Q

Conversion of IMP to AMP and GMP. What E sources do each of them need?

A

IMP →AMP : needs GTP
IMP → GMP : needs ATP

Both AMP and GMP are the end products that inhibit the first steps in both pathways
- that way IMP makes more of which ever one is needed more

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15
Q

Mycophenolic acid

A

The drug is a reversible inhibitor of IMP dehydrogenase which catalyzes the first step in IMP → GMP synthesis

  • deprives rapidly proliferating T + B cells of nucleic acid components
  • good 4 immunosuppressants
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16
Q

Conversion of nucleoside monophosphates to nucleoside diphosphates involve which enzyme?
AMP → ADP
GMP → GDP

What about diphosphates to triphosphates?
GDP → GTP
CDP → CTP

A

AMP → ADP
- adenylate kinase
GMP → GDP
- guanylate kinase

GDP → GTP
CDP → CTP
- both: nucleoside diphosphate kinase

17
Q

APRT and HGPRT

A

Both enzymes convert purine bases to nucleotides + use PRPP as source of ribose 5-phosphate
Irreversible rxns

Hypoxanthine → IMP
Guanine → GMP
- both use HGPRT

Adenine → AMP
- uses APRT

18
Q

Lesch-Nyhan syndrome

A

Complete deficiency of HGPRT
Inability to salvage hypoxanthine or guanine and end up excessive uric acid (end products of purine degradation)
- heritable cause of hyperuricemia
- also causes ↑ PRPP levels, ↓ IMP and GMP levels
(PRPP isnt used up to make IMP and GMP), which causes increased de novo purine synthesis

  1. Hyperuricemia
  2. Uroacid stones in kidney
  3. gouty arthritis
  4. motor dysfxn
  5. cognitive deficits
  6. behavioral distubances (self mutilation)
    - biting lips/fingers
19
Q

main enzyme required for reduction of purine and purimidine nucleoside diphosphates

  • what does it do
  • how is it inhibited? Activated?
A

ribonucleotide reductase
- responsible for maintaining balanced supply of DNA required for DNA synthesis

Binding of nTPs to substrate specificity sites (2nd site on E), regulates conversion of ribonucleotides to deoxyribonucleotides:

  • binding of dATP to enzyme inhibits activity + prevents reduction of any of the 4 nDPs
  • binding of ATP activates enzyme
20
Q

Adenosine deaminase ADA deficiency

A

ADA deficiency causes a type of severe combined immunodeficency (SCID), involving T + B cells, and NK cell depletion (lymphocytopenia)
- adenosince cannot make inosine

  • untreated: can die b4 2 yrs
    tx: gene therapy
21
Q

Gout can be dx by?

A

presence of NEGATIVELY birefringent monosodium urate crystals in aspirated synovial fluid
- examined by polarized light microscopy

22
Q

Which of these, purine synthesis or pyrimidine synthesis is the ring synthesized first, before attaching the phosphate (which is donated by PRPP)?

A

Pyrimidine: ring is synthesized before being attached to ribose 5-P

(Purine : constructed on a preexisting ribose 5-phosphate)

23
Q

Regulated step of pyrimidine synthesis

A

synthesis of carbamoyl phosphate from

Glutamine and CO2 + 2 ATP via carbamoyl phosphate synthetase II

24
Q 
CPS I
cell location
pathway involved
source of N
regulators
A

CPS1

cell location: mitochondria
pathway involved: urea cycle
source of N: ammonia
regulators: activator (N-acetyl-glutamate)

25
Q 
CPS II
cell location
pathway involved
source of N
regulators
A

CPS II

cell location: cytosol
pathway involved: pyrimidine synthesis
source of N: amide group of glutamine
regulators: activator (PRPP), inhibitor (UTP)

26
Q

Both purine and pyrimidine synthesis requires what 3 things as essential precursors?

A

glutamine
aspartic acid
PRPP

27
Q

UMP is necessary for pyrimidine synthesis. How is UTP made?

A

Glutamine + 2 ATP + carbamoyl phosphate synthetase II →→ OMP → UMP → UDP → UTP

(note that UDP is a substrate for ribonucleotide reductase, which generate dUDP, which can be P to dUTP)

28
Q

First step in purine synthesis vs first step in pyrimidine synthesis

A 
purine:
- committed step
uses PRPP + N from glutamine
(PRPP is used as an "activated pentose" that provides the ribose-phosphate group for de novo purine and pyrimidine synthesis and purine salvage)
- end products: AMP and GMP
Pyrimidine:
- regulated step
- production of carbamoyl phosphate by carbamoyl phosphate synthetase II
(activated by PRPP)
- end products: UMP →TMP
29
Q

Gout results from what?

A

build up of uric acid, which is an end product of purine degradation.
- if gout is present, then there could be an overproduction of the end products of purine degradation

(pyrimidine met is NOT assoc. w/ uric acid production)
Purine salvage (not degra) decreases uric acid production

Dems Unit 02 - 02 (20 decks)

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