Urea Cycle

2 sources of amines for urea cycle

1. aa cat

2. asp

+ N balance

amt protein ingested > amt protein degrad in normal cell turnover

• amt circulating aa is ~ constant, excess can be ox/excreted in feces

- N balance

ingested protein < amt degrad by cell in normal turnover

• amt circulating aa decreases over time

urea

nontoxic, water sol, excreted in urine; major nitrogenous excretory prod

uric acid

degrad prod of purines, creatine phosphate, byprod of energy storage in some tissues, conv to creatinine & excreted in urien

kwashiorkor synd

sufficient cal intake but insufficient protein intake → ab distension (ascites) due to decreased protein, esp albumin (decreases osmotic pressure → fluid leaks to cavities)

cachexia

extreme ox of aa from muscle proteins → muscle wasting

all aminotransferases req what cofactor?

PLP/vit b6

ALT (ALA aminotransferase)

Ala → aKG → pyruvate + Glu (reversible)

AST (Asp aminotransferase)

ASP → aKG → OAA + Glu (reversible)

• involves chiff base int

glu dh

removes amine group from glu → ammonium ion

allosteric activator of glu dh

ADP (low en st)

allosteric inhib of glu dh

ATP, GTP

gln synthetase

Glu → Gln

in most tissues

5 enzymatic steps of urea cycle

1. CPSI****

2. ornithine transcarbamoylase

3. argininosuccinate synthetase

4. argnininosuccinate lyase

5. arginase

major reg enzyme of urea cycle

CPS I

s of CPS I

bicarb + NH4 + 2ATP

prod of CPS I

carbamoyl phosphate

substrate of ornithine transcarbamoylase

carbamoyl phosphate + ornithine

prod of ornithine transcarbamoylase

citrulline (leaves mit)

substrates of argininosuccinate synthetase

ASP + citrulline

prod of argininosuccinate synthetase

argininosuccinate

s of argininosuccinate lyase

argininosuccinate

prod of argininosuccinate lyase

ARG + fumarate

s of arginase

ARG

prod of arginase

urea + ornithine (goes back to mit)

treatment for disorder affecting first 3 steps of urea cycle

1. CPSI

2. ornithine transcarbamoylase

3. argininosuccinate synthetase

Ucephan

treatment for disorders affecting last 2 steps of urea cycle

4. argininosuccinate lyase

5. arginase

supplement w ARG

reg of urea cycle

feed forward reg— substrate avail (increase in ammonia increases urea)

short-term reg of urea cycle

1. CPSI is activated by NAG—ARG stimulates NAG synthase

2. ARG stimulates arginase (feed forward reg)

amino acids, esp ALA are major source of C for ___________

gluconeogenesis

urinary excretion of urea is _____ in fasting state

increased

effect of glucagon on urea cycle

stimulates Ala transport into liver by activating transcription of transport systems

urea products __________ from fasting to starvation

decrease (due to glucose-sparing)

clinically significant impact of urea cycle disorders

accumulation of ammonia → NS toxicity

what amino acid builds up when urea cycle is blocked?

glutamine

• not broken down to Glu and alpha-KG so these are reduced

ammonia _______ glu due to …

decreases / due to greater conv of Glu → Gln via Gln synthetase

essential trtmnt for all urea cycle disorders

low protein diet

• decreases amino acid breakdown & rel of ammonia

for treating disorders that affect ornithine transcarbamoylase or argininosuccinate synthetase, must administer drugs that will form ______________

conjugates with amino acids

• ca nbe excreted

• commonly Gly and Gln