Urea Cycle

• After amino acid deamination, we are left with free ammonia, but it is toxic! So we transport it via glutamine to the liver for the urea cycle.
• Glutamine synthetase can be used to make glutamine to transport ammonia in the blood, and works by first activating glutamate with phosphorylation by ATP, and then substituting the phosphate group for ammonia to form glutamine.
• The urea cycle is used to rid of toxic ammonia and eliminating it via urea.
• Overall, urea cycle takes ammonia, bicarbonate, and aspartate and produces urea and fumarate. It requires 3 ATP, 2 for phosphorylation and 1 for adenylation.
• First step: carbamoyl phosphate synthetase (CPS) produces carbamoyl phosphate in 3 steps.

  1. use first ATP to activate bicarbonate (form carboxyphosphate)
  2. sub phosphate for ammonia, forming carbamic acid
  3. use second ATP to phosphorylate

  
• carbamoyl phosphate synthetase has a tunnel that connects its two active sites:

  1. first active site for first two steps to form carbamic acid
  2. second active site to phosphorylate

  So each active site binds ATP. This structure is necessary because the carbamic acid intermediate is unstable.
• Which enzymes of the urea cycle act in the mitochondria?

  Carbamoyl phosphate synthetase and ornithine transcarbamoylase.

  
• Arginase requires Mn2+, where its role is to

  1. polarize the O-H bond in water and facilitate deprotonation to OH- (ultimately help activate water)
  2. orient the substrates together

  
• In the case of an arginosuccinase deficiency, it is helpful to consume excess arginine to continue cycling through (regenerate ornithine). The arginosuccinate can be excreted.

  
• Aspartate can be supplied from transamination.

  Fumarate can be fed into the TCA cycle, creating oxaloacetate either for more TCA, or gluconeogenesis, or even for aspartate (use transamination!) for the urea cycle.

  
• Fill in the processes.

  A) urea cycle

  B) TCA

  C) transamination

  D) gluconeogenesis