Amino Acid Degradation and Synthesis II Flashcards
What is the major carrier of nitrogen in the blood?
glutamine
What is glutamine made from for transfer?
NH4+ is added to a-ketogluterate (through ATP and NADPH) to make glutamine, which then goes to the liver from peripheral tissue where it is deaminated twice to give off NH4+ to reform a-keotgluterate
What is the fate of the Nh4+ groups given off during the reconversion of glutamine to a-ketogluterate in the liver?
made into urea and eventually urine
What is another nitrogen transporters that gives nitrogen products to the production of urea?
alanine (gives off NH3). In the alanine cycle, alanine goes to the liver from peripheral tissue in fasting conditions and the ALT enzyme trans-aminates alanine to pyruvate (for gluconeogenesis) which causes NH3 to be given off. Most of the NH3 enters the urea cycle
Alanine and glutamine pass their AAs to what compound for them to enter the urea cycle?
glutamate
What are the significances of NH4+ and NH3 in the urea cycle?
NH4+ is the predominant form of ammonia in the body due to its high dissociation constant (9.3), but NH3 is important because it is the form that can cross cell membranes (NH4+ cannot because it is charged)
T or F. High levels of ammonia can be toxic
T. Normal level of ammonia in blood = 30-60 mM
The majority of nitrogen in urine is present in what form?
urea
Where does the urea cycle occur?
some steps in mitochondria and some in the cytosol. ALL in the liver
What is the first step in the urea cycle?
HCO3- made from H2O and Co2 is combined with NH4+ to form carbamoyl phosphate (through input of 2 ATP)
What enzyme catalyzes the conversion of HCO3- and NH4+ to carbamoyl phosphate?
carbamoyl phosphate synthetase I (CPSI)
What is the second step in the urea cycle?
carbamoyl phosphate is combined with ornithine to make citrulline (by giving off a phosphate group)
What enzyme catalyzes the conversion of carbamoyl phosphate and ornithine to citrulline?
ornithine transcarbamoylase (OTC)
What happens to the citrulline?
it moves OUT of the mitochondria into the cytosol (via exchange of ornithine into the mitochondria)
What is the source of the second nitrogen in urea (remember that NH4+ from glutamine/alanine is the first)?
aspartic acid (aspartate)
What happens to the citrulline once in the cytosol?
it combines with aspartic acid (via ATP input) to form argininosuccinate
(enzyme is argininosuccinate syntheses)
What happens to argininosuccinate?
it splits up to form fumarate and arginine as part of the Krebs Bi-cycle (via the enzyme argininosuccinate lyase)
fumarate then enters the TCA and arginine continues along the urea cycle
What happens to the arginine?
it is converted to ornithine by giving off urea (via the enzyme arginase). The ornithine is then transferred back to the mitochondria (via exchange with citruline leaving) and then can be re-used in the next cycle (via combo with carbamoyl phosphate)
How do you measure the urea cycle?
BUN- blood urea nitrogen (normal 250-700 uM)
high BUN= renal failure
low BUN= deficient urea cycle
What is the most common deficiency of the urea cycle?
OTC deficiency
What is OTC deficiency?
x linked disorder
results in high ammonia levels in the blood, high rotate (orotic acid), and low citrulline
which can lead to neuronal damage and mental retardation
What happens to carbamoyl phosphate when there is an OTC deficiency?
it will be converted to orotate which is used from pyrimidine synthesis
What is the treatment for OTC deficiency?
Need early intervention. Generate low nitrogen levels by:
1) Low-protein diet
2) Drugs that conjugate (react with) amino acids
- Benzoic acid and phenyl butyrate. Conjugated AAs are then lost by excretion
-Nitrogen used to resynthesize amino acids that are lost
What is the main source of arginine in the body?
the urea cycle
How is tyrosine made?
phenylalanine via phenylalanine hydroxylase (adds a hydroxyl group)
What cofactor does phenylalanine hydroxylase use?
tetrahydrobiopterin (BH4)- synthesized by GTP
Blocking the action of phenylalanine hydroxylase causes what?
PKU- phenylketonuria (inreased levels of Phe)
deficiency in the synthesis of BH4 can also cause PKU
What happens to tyrosine once synthesized?
it can be converted to p-hydroxyphenolpyruvate via tyrosine aminotransferase
A block in tyrosine aminotransferase can lead to what?
Tyrosinemia II- can lead to neurological problems
What cofactor does tyrosine aminotransferase II use?
PLP (paradoxyl phosphate)
What is the treatment for Tyrosinemia II?
diets/foods low in phenylalanine and tyrosine
What happens to p-hydroxyphenolpyruvate once synthesized?
it can be made into homogentisate
What happens to homogentisate once synthesized?
it is further converted via homogentisate oxidase (product unimportant)
A block in the activity of homogentisate oxidase leads to what?
Alcaptonuria
What is a clinical sign of alcaptonuria?
urine forms a dark pigment when exposed to air
can lead to arthritis
What is Tyrosinemia I?
a disease caused by a block in the activity in fumarylacetoacetate hydrolase (which catalyzes the final step in the phenylalanine/tyrosine pathway from an intermediate to fumarate and acetoacetate
How is alanine made?
transamination from pyruvate
How is serine made?
from 3-phosphoglycerate (a glycolysis intermediate) or from glycine
What glycolysis intermediate can serine be made into?
2-phopshoglycerate
How can glycine be made?
serine can be converted to glycine via serine hydroxymethyl transferase (rxn is reversible)
What cofactors does serine hydroxymethyl transferase use?
PLP and tetrahydrofolate (FH4)
What is FH4?
tetrahydrofolate is the reduced form of folic acid (folate)- reduced form is the most common in the body
What is folate used for?
glycine synthesis, nucleotide metabolism, and transfer of carbon to vitamin B12
How is cysteine made from serine?
homocysteine is added to serine using PLP to make cystathionine, which can react with PLP to form cysteine
Vitamin B12 is aka?
cobalamin- coordinated cobalt
obtained from meat, eggs, dairy, fish
What does vitamin B12 do?
cofactor for 2 rxns:
1) transfer of methyl group from FH4 to homocysteine to form methionine
2) rearrangement of methylmalonyl-CoA to generate succinyl-CoA
How can homocysteine be made from methionine (essential and obtained from diet?
via conversion to s-adenylomethionine (SAM) (using ATP and giving off phosphate groups) and then conversion to s-adenylohomocysteine (SAH) by SAM giving off a methyl group. SAH is then converted to homocysteine by giving off adenosine
What does FH4 do in terms of homocysteine and methionine?
FH4 can transfer a methyl group to vitamin B12 which can then pass the methyl group to homocysteine to form methionine
What is homocysteinemia?
high homocysteine levels in the blood
describes a biochemical state- not a specific disease
high levels of homocysteine will also lead to homocystinemia and homocystinuria and high levels of methionine in the blood (homocysteinuria NOT observed)
high levels an be a good diagnostic marker for cardiovascular disease (maybe better than LDL)
What is the classical cause of homocysteinemia?
deficiency in cystathionine B-synthase (CBS) enzyme used to produce cystathionine (and eventually cysteine)
can also be caused by deficiency in the cofactors involved (FH4 and vitamin B12)
What is homocystine?
two homocysteine molecules connected by sulfide bonds (will have high levels with homocysteinemia
What are common homocysteinemia clinical manifestations?
pathology is variable
dislocated optic lens (interfere with collagen function), abnormal blot clotting
What is the treatment for homocysteinemia?
low methionine diets and oral vitamin B6 (which is a precursor for PLP)
How do you make glutamate?
transamination with a-ketogluterate
How do you make glutamine?
glutamate + NH4
How do you make aspartate?
transamination with OAA
How do you make asparagine?
aspartate + glutamine
How do you make proline?
from glutamate
