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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


Glutamate dehydrogenase

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


Glucogenic breakdowns

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


Thyroid chemistry

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


Porphyrin 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


Heme degradation

- 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


Bilirubin glucuronyl-transferase

Low in infants, especially premature
- fluorescent light converts bilirubin to more polar products and allows removal similarto conjugated bilirubin