Urea Cycle

How are AAs produced?

De novo synthesis, digestion of dietary proteins, and intracellular protein digestion.

What can AAs feed into?

• Protein synthesis

• Degratin/enery source - NADH/FAHD2 productions, TCA int, gluconeo, keton bodies

• synthesis of other biomol - Pur/Pyr, phosphoatidyl serine, sphingosine, thyroxine epi, melatonin, Ach GABA, Heme , histamine, crestine, carnATiNE

• Cell signaling - glycine/glutamate

• Nirtrogen extcretion

Describe to your patient what a postive vs negative nitrogen balancce is?

• Posititve — N intake >extretion (growth, infancy-ado, preg, rec from maltrutution)

• Negative N intake < excretion (illness/mal/BURNS)

WHat is nitrogen seen as in the liver, kidney, and muscles?

• urea cycle (liver)

• glutanmine (kidney)

• Creatine phos (muscle)

• Also as purines

What do we see in patient A whose has kindey damamge and patient B who has liver damage and patient C who is pregnant, in term of blood urea nitrogen, creatine, uric acid, and ammonia?

What are the sources of ammonia in the body?

Glutamine, Monoanibes, purines/pyr, diet, transanmin rens, urea, other AAs, degration of neurotramsitters.

Describe the degration of AAs?

Removal of nitrogen

• via transmination, deamination, or admidation

Clearnace of NH4+

• urea ccyle ( ie ammonia is toxic)

Util of the carbon backbone

• fed state - son of glcyogen fo trigly

• fasting - enegery prod

***Urea cycle - one N comes for NH4, one from Asp, and carbon camones for CO2

How is nitrogen ripped away from the innocent AA

Denamination - removal of alpha amino of (glutamate, G, S, T, H) as NH4+

***Goes in the reductive direction in the liver and kindey

Occurs in the oxidative direction in other tissues

• All done via glutamate dehydrogenase

Deadmidation - removal of amide form glutamine and aspragone as NH4+

• Import in the kindey, most of the NH3 in urine, NH3 balances pH in urine

What is the main pathway of nitrogen removal?

Transamination - transfer of alpha amino from an aminot to a alpha keto

• Generally on glutatmate, reverabale, cat via trabnsmainases (amintransases)

• Uses PLP ie B6

Using aminotransferases as diagnostics.

Using AST or ALT in the liver , indicitaes liver damage, ALT more specific, AST also found in MI patients

What is the role of glutamate in nitrogen removal?

Collects N from AA via transmaination

Provides NH4 via deamination of glutmatated dehydrogenase

N to urea indirectly via transsmin oxaloacetate in Asp

Precur for allosteric act of the urea cycle

Glutamate Gathers, Gives, and Governs"

• Gathers N via transamination

• Gives N via deamination or aspartate

• Governs urea cycle by making N-acetylglutamate

Where does the urea cycle take place and why is this the ulimate place of N?

Only in the liver, AA N is carried to the liver via Alanine > glutamine and other AA to a lesser extent. —> urea then trasnported to the kidney and extreted in the urine (some via small intestines)

Who be using all the glutamate and who be making dis shit?

Using : Kidneys, gut, immune cells, and liver

Making: Muscle and brain

***NH4 used via glutamine syn, made via glutaminase and glutamate dehydro

Why do we trasnport alanine to the liver?

• Removal of N via the urea cycle

• Gluconeo

Sources: Main muscle (via protein degration and transanim and kidney +intenstine

• glutamine —>glutamate —Alanine

  ………Glutaminase …..ALT……..

A patient comes in with toxic amount of ammoina in thei blodd, descibre the mechanism which would normally be in work to keep these ammonia levels in check.

• Transaniation rxn collect N on glutamate (safe if not free)

• Glutamate dehydrogenase (NADH/NADPH), glutamine synthesis (ATP) main brain detox, carbamoyl phos synthesis 1 (ATP)1 step in urea syn

Where is the location of the urea cycle start and finish?

• Starts in the mito and finished in the cytosol

Describe carbamoyl phos synthesis?

Cat via carbamoyl phos synthetase I ( CPSI) —> RL and commitment step

• in the mito, uses 2 ATP (irreversible), allos reg via N acetylgutamate (NAG) (act via arginine)

• Act via agrinine and N acetyl glutamate

Clinical sig : Type I hyperammonemia

**Also can be syn from glutatmine and CO2 via CSPII in the cyctol —>pyrimidine synthesis

Describe citrullinne synthesis

Cat by ornithine transcarbmoylase (OTC)

• In the mito, transpofrted via ornithine translocatase —>cytosol

Clinical rel: Ornithine transcarbamoylase —> T2 hyperammonemia

orithine translocase —>hyperorithemia hyperammonemia - Homocitrullinuria (HHH) syndrome

Describe argininosuccinate synthesis?

Cat via arginosuccinate sythetase

• in the cytosol, req 1 ATP, Asp—>ammonia

Clinical rel: Def = cirtullinemia T1

**T2 is caused by def citrin which is a mito glutamate/aspartate shuttle

Describe arginine synthesis.

Cat via. argininosuccinate lyase

• in the cytosol, only way its produced the human body, released furmarate —→OAA—>Asp

Clinical Rel: Def = argininosuccinyl acidemia

What happens when arginine is cleaved?

Cleaved into urea and ornithine, Cat via arginase in the cytosol, orthinine moves back to mito and reacts with carbmoyl phosphate.

Clinical rel: Def causes argininemia

Arginine can go to protein syn or NO syn

How is this complicated ass cycle funded in terms of energy?

4 phosphate bonds are broken making this irreversible

• Energy remvoed if furmurate —>malate—>OAA

What are some regulation steps of the urea cycle?

N acetyl glutamate is a alloesteric ac t of carbamoyl phosphate synthetase I (CSPI)

• Itself act via high arginine levels

High protein diet and excess degradation ie fasting will increase urea syn (increased Arg and ssyn of urea cycle enzymes)

Conc of subs and inter

How is the urea cycle used during fasting?

• Your muscles are broken down and AA —> Liver —> converted to glucose

• N of used AA —> urea

• When starving brain —> switches glucose —>ketone bodies(from FAs)

• Decreased AA utilization —> decreaaed urea

What are the differecnes between primary and secondary type of hyperammonemias?

Primary - enyzmes in the urea cycle are defective

Secondary - main cause is liver failure (cirrhosis, hep, hepatoxins), heaptocyctes are fucked up, genetic defects can cause this ie beta oxi def

Expand on primary hyperammonemias? Also how can we really distuingish between these diseases?

Type 1: (CPSI or N acetylgltamate synthease def)

Type 2: (ornithine transcarbmoylase ) (X linked)

Citrullinuria T1: arginosuccinate synthetase def

Arginosuccininic acidemia:arginosuccinate lyase def

Argininemia: arginase def

How do we distinguish between the different causes for primary hyperammonemias?

High urine orortate in CPSII

HHH with extremem high blood ornithine nad homocituiline levels.

WHat are some exmaples of AA supplementation?

Arginine - All primary hyperamm will result in low Arg expect for arginase def

• Promtes prod of N aacetyl glut so CPSI can he lp for second ammon

Citrulline - T1 and T2 hyperammonemia. Captures Asp so one N can be excreted

N carbamoylgluatamate - angonist for CSPI in case of N acetylglutamtate synthetase def

How do we reduce the N load on the urea cycle?

Low protein diet, avodi fastin - limit AA degrad

Scavanger drugs - conjugate AAs and taeget for excretion

• Benzote + glycine —> hippuric acid —>exc

• Phenylbutyrate + glutamine —> phenylacetylglutamine —> exc

Reducing ammonia from micro flora

• Bat ureases in gut generates ammonia

• Lactolose laxactive decreases pH so ammoina connot be absorbed, *** ureases inhale red N via this source.