L17 - Urea Cycle

Two parts to AA processing

Urea processing and Carbon Skeleton processing

Activation of Urea Cycle Pathway

Activation via CPS-I

NH₄⁺ + 2ATP + HCO₃^- → Carbamoyl phosphate + 2ADP + P_i via Carbamoyl Phosphate Synthetase (CPS-I)

Ammonia assimilating: Incorporation of ammonia into another compound to reduce ammonia concentration

Occurs in the mitochondria

First Part of Urea Cycle Pathway

Formation of Citrulline

Ornithine + Carbamoyl phosphate → Citrulline + P_i via Ornithine transcarbamoylase (OTC)

Occurs mostly in liver mitochondria, 5-10% may occur in kidney

Citrulline diffuses passively

Second Part of Urea Cycle Pathway

Formation of Argininosuccinate

2 steps:

1. Citrulline + ATP → Citrullyl-AMP + PP_i via Argininosuccinate synthetase

2. Citrullyl-AMP + Aspartate → Argininosuccinate + AMP via Argininosuccinate synthetase

Second N of Urea is donated by aspartate (D)

Occurs in cytosol

Third Part of Urea Cycle Pathway

Formation of Arginine

Argininosuccinate → Arginine + Fumarate via Argininosuccinase

Occurs in cytosol

Fourth Part of Urea Cycle Pathway

Formation of Urea

Arginine → Urea + Ornithine via Arginase

Ornithine is taken back to the mitochondria to repeat the cycle

Occurs in cytosol

Ornithine diffuses passively

Krebs-Bicycle

Urea and TCA cycle are interlinked

Linking pathways are referred to as aspartate-argininosuccinate shunt

This shunt links the carbon skeleton of AA, allowing degradation of both AA parts through the Urea and TCA cycle

Many enzymes like Malate dehydrogenase and Fumarase allows certain intermediates to be transferred between cytosol and mitochondria for other uses

Malate-aspartate shuttle regenerates OAA and forms D for the U cycle

Also decreases energetic load of urea cycle by providing reducing equivalents (Used by mitochondria to produce ATP)

Aspartate (TCA) + Citrulline (U) → Agininosuccinate (U) → Arginine (U) + Fumarate (TCA)

OAA ←→ D via AST

Regulation of Urea Cycle

High protein diet induces U cycle enzyme synthesis:

1. Glucagon stimulates biosynthesis of all urea cycle enzymes after a protein-rich meal

2. A, G, M, & C all stimulate glucagon release

3. AA catabolism reduces ammonia load and increases OAA and α-KG for gluconeogenesis

High levels of E (substrate) and R (activator) triggers N-actylglumatmate (NAG) synthesis

1. CPS-I is allosterically activated by NAG

2. When AA catabolism increases, E and NAG increase

N-Acetylglutamate Synthesis Pathway

Acetyl-CoA + E → NAG via N-Acetylglutamate synthase (NAGS); Allosterically Activated by R

NAG allosterically activates CPS-I