INtro Amino acids - disposal of Nitrogen 19 Flashcards
Any aa in excess of biosynthetic needs are rapidly degraded. First and second phase of catabolism involves?
- transamination via aminotransferase
- removal of a-amino group grom a-amino acid - oxidative deamination
- forms ammonia and a-keto acid “carbon skeleton” of aa
- presence of a-amino group keeps aa safe from oxidative breakdown.
- a-ketoglutarate is the ammonia (amino group) acceptor and becomes glutamate
Cystinuria
carrier system is defective and cannot uptake COAL
- cystine
- ornithine
- arginine
- lysine
all 4 appear in urine
- most common genetic error of amino acid transport
transamination
funneling of amino group to glutamate
transfer a-amino group from a-amino acid to a-ketoglutarate –>
a-keto acid + glutamate
Two sources of urea nitrogen
ammonia
aspartate
Two most important aminotransferases
Alanine aminotransferase (ALT)
Aspartate aminotransferase ( AST)
ALT
- fxn
Alanine aminotransferase (ALT)
- transfer amino group of alanine to a-ketoglutarate
- generates pyruvate + glutamate
(glutamate is the “acceptor” of Nitrogen from alanine)
- readily reversible
AST
- fxn
Aspartate aminotransferase (AST)
- transfers amino groups from aspartate to a-ketoglutarate
- makes oxaloacetate and glutamate
aminotransferases require the coenzyme ____. Which is a derivative of ____.
Fxn?
pyridoxal phosphate (PLP)
- derivative of Vit B6
- “holds” the amino group during transfer
equilibrium constant of transamination rxn? Why is this imp?
K = 1
Allows rxn to fxn in both:
- aa degradation (via a-amino group removal) and
- aa biosynthesis (via addition of amino group to carbon skeleton of a-keto acid)
Why are elevated AST and ALT levels important?
Aminotransferases are normally intracellular enzymes
- presence of elevated levels indicates dmg to cells rich in these enzymes
- ALT more sensitive for liver than AST
Oxidative deamination of amino acids (ie: glutamate –> a-ketoglutarate) are done via which enzyme?
glutamate dehydrogenase
- this frees an ammonia (NH3)
- provides an a-keto acid for metab.
(usually in liver and kidneys)
Diff between transamination and oxidative deamination
- enzyme
- substrates
Sequential actions:
transamination
- aminotransferases
- transfer -NH2 of a-amino acid (with a-ketoglutarate) to glutamate
oxidative deamination
- glutamate dehydrogenase
- ox deam. of glutamate to regenerate a-ketoglutarate and release amino group as ammonia, and make NADH/NADPH (3 things)
These rxns also free up a-keto acids which can enter central pathway of E metabolism.
After ingestion of meal containing protein, glutamate levels _____ in the liver, and the transamination rxn proceeds in which direction?
Meal –> Glutamate rises
- rxn proceeds in direction of aa degradation and formation of ammonia
GTP is an allosteric ______ glutamate dehydrogenase.
ADP is an allosteric _____ of glutamate dehydrogenase
(note that glutamate dehydrogenase is responsible for oxidative deamination of a-ketoglutarate and glutamate)
GTP: inhibitor
ADP: activator
When E levels are low (high ADP, low GTP), then glutamate dehydrogenase is _____.
High
this facilitates E production from the carbon skeletons derived from aa.
How do Hu transport ammonia from the peripheral tissue to the liver for its conversion to urea?
- Glutamate gets converted to Glutamine via Glutamine synthetase (which adds an extra NH3, and uses ATP doing so)
- GLutamine is a nontoxic transporter of ammonia - Glutamine is transported from most tissues –> blood –> Liver
- Glutamine in the liver is cleaved by glutaminase to make glutamate and free NH3 again!
- NH3 can be excreted as Urea in the liver
How do amino acids in muscles contribute to making pyruvate in the liver to produce glucose?
GLucose-alanine cycle
Pyruvate in the muscle can be transaminated by ALT to alanine. Alanine can then move to blood to liver.
- Ala is then tranaminated to pyruvate.
- This pyruvate can be used to undergo gluconeogenesis and make glucose.
Urea
major disposal form of amino groups derived from amino acids
- accounts for 90% of nitrogen containing components of urine.
- produced by the LIVER –> transported in the blood to kidneys for excretion in the urine
Urea is supplied by which two nitrogens? What serves as the precursor to both nitrogens?
- free ammonia
- N of aspartate
- glutamate is the immediate precursor of both ammonia
First two rxns of Urea cycle
- where
- what
In mitochondria
- formation of carbamoyl phosphate
- formation of citrulline
What substrate in the urea cycle has to form before its transfer from the mitochondria to the cytosol?
citrulline
(from Ornithine + carbamoyl phosphate via ornithine trans-carbamoylase)
- moves via cotransporter with ornithine (citrulline out, ornithine in)
Places where ATP is consumed in urea cycle
1+2. first step of urea cycle
- CO2 + NH3 + 2ATP –> carbamoyl phosphate
- 3rd step
- Citrulline + aspartate + ATP –> arginosuccinate
Immediate precursor of urea
arginine (via arginase) –> urea
(from arginosuccinate)
- in LIVER
RLS of the urea cycle
First step
N-Acetylglutamate is essential activator for Carbamoyl Phosphate synthetase I
After ingestion of a protein rich meal, levels of N-acetylglutamate ______.
increases
This activates carbamoyl phosphate synthetase
- increased rate of urea synth.
Hyperammonemia (ammonia intoxication) sx
- tremors
- slurring of speech
- somnolence
- vomiting
- cerebral edema
- blurred vision
- coma/death
Acquired hyperammonemia
Conversion of ammonia to urea is severely impaired
liver disease is a common cause
- ie: hepatitis, hepatotoxins (OH)
- cirrhosis (portal blood shunted to systemic circulation with no access to liver)
*note: elevated glutamine always accompanies hyperammonemia bc its a nontoxic storage and transport form of ammonia
COngenital hyperammonemia
Ornithine trans-carbamoylase deficiency
- x-linked
- failure to synthesize urea –> hyperammonemia in first weeks following birth
- high morbidity
*note: elevated glutamine always accompanies hyperammonemia bc its a nontoxic storage and transport form of ammonia
3 amino acid : a-keto acid pairs commonly encountered in metabolism
alanine/pyruvate
aspartate/oxaloacetate
glutamate/a-ketoglutarate
amino nitrogen of dietary protein is excreted as ____
urea.
- urinary urea is increased by a diet rich in protein
What significant part of the urea cycle takes place in the mitochondria?
CO2+ NH3 + 2ATP + carbamoyl phosphate synthetase I → carbamoyl phosphate
carbamoyl phosphate + Ornithine → Citrulline
Urea cycle happens where?
Liver
Glutamate dehydrogenase goes both ways ;) what two things does it interconvert?
Glutamate → a-ketoglutarate
and visa versa
*glutamate has NH3, a-ketoglutarate does not
