Flashcards in Protein Biochemistry II Deck (20):
Where does the urea cycle occur?
Mitochondria and cytosol via the antiporter ORNT1
Kickstart with ornithine in the mitochondria.
Ornithine is transported in while citrulline is transported out
Overall Urea Cycle Rxn
3 ATP + HCO3 + NH4(N) + Aspartate --> 2ADP + 2Pi + PPi + fumarate + urea
1st ATP in urea does what?
Activates soluble form of CO2 (carbamoyl phosphate)
What is the control point for protein catabolism?
1. Carbamoyl phosphate synthetase I
2. Uses 2 ATPs to add one phosphate and ammonia
3. 10 mutations found on this enzyme lead to early onset of associated |urea cycle disorder"
How is carbamoyl phosphate synthetase I regulated?
1. Activator - N-acetylglutamate.This is activated itself by arginine.
2. Two ATP binding sites
Transport of ammonia
Performed by glutamine (glutamate can hold 2 nitrogens = glutamine)
Goes from peripheral tissues to:
1. Kidneys - removed in the form of urine ammonia
2. Liver - removed in the form of urea (through blood to kidney)
Muscle: Ala produced for transport to liver
1. Allosterically regulated (ATP & GTP inhibit and ADP & GDP activate) and serves as another control point for catabolism.
2. Genetic mutation in ATP/GTP binding site results in hyperinsulinism-hyperammonemia syndrome (elevated levels of ammonia in blood = gain of fxn mutation)
Cross-talk in urea cycle
NO is a neurotransmitter derived from Arginine via NO synthase
NO is a dilator; activator of guanyl cyclase
Arginine --(NO synthase)--> Citrulline + NO
Arginine & urea cycle
Arginine --> Creatine phosphate and Ornithine via amidinotransferase, methyltransferase, kinase
Glucogenic vs. Ketogenic
Glucogenic - derive carbon source; pyruvate or Krebs cycle intermediate
Ketogenic - derive acetyl-CoA; no NET production of glucose
Asparagine --> aspartate via asparginase
Note: this is an anti-cancer drug because it deprives cells of Asn
Defect in breakdown of branched chain AA
(branched chain alpha keto acid dehydrogenase complex is defective)
Leu - Ketogenic
Ile - Both
Val - Glucogenic
Leads to high concentrations of keto-acids in urine
T4 made from tyrosine; is a prohormone and is converted to T3
Both are transported via TBG in the blood
Made by the suicide of thyroglobulin (Tg) -->Thyrodine peroxidase iodinates Tyr --> proteolyzed and carried through TBG
TSH: stimulates I- uptake; stimulates release of T4, T3
Thyroid peroxidase: Oxidizes I- to I2
Tg: Contains Tyr reisdues iodinated to form T4, T3
TBG: Transports T4, T3
Defects in heme synthesis
- Heme is a porphyrin produced in liver
- porphyrins are cyclic molecules that bind Fe2+
- porphyrias are inherited defects in heme synthesis
6 enzymes involved in heme production
** Iron binding to porphyrin ring is catalyzed by ferrochelatase to make heme.
Regulation of heme synthesis
1. Initial reactions ALAS1, ALAS2 are inhibited by end-product, and ALA dehydratase is Zn dependent
2. Lead posioning --> anemia; can replace Zn in ALA dehydratase and inactivate enzyme, also can replace FE2+ in ferrochelatase
Where does heme synthesis occur?
Some in mitochondria, some in cytosol
- degraded to bilirubin
- high bilirubin leads to jaundice
- bilirubin is also an anti-oxidant
Heme-->biliverdin-->bilirubin (more soluble)
Glucoronic acid at birth
Not made when you are born so you need to have more soluble forms of biliverdin and bilirubin
If not very soluble, attach it to glucoronic acid to make it more soluble and get it out of the body