AA Metabolism (Biochem) Flashcards
1
Q
How does the body get rid of excess N
A
- through the urine
- most excess N is converted to urea in the liver and goes through the kidney where it is eliminated in urine
- the kidney adds small quantities of ammonium ion to the urine in part to regulate acid-base balance, but also to eliminate N
- amino groups released by deamination runs form ammonium ion (NH4+) which must not escape into peripheral blood
- hyperammonemia has toxic effects on the brain (cerebral edema, convulsions, coma, death)
- most tissues add excess N to the blood as glutamine by attaching ammonia to the gamma-carboxyl group of glutamate
- Muscle sends N to the liver as alanine and smaller # of other aa including glutamine
2
Q
Glutamine Synthetase
A
- in most tissues
- captures excess N by laminating glutamate to form glutamine
- IRREVERSIBLE Rxn
- Glutamine (relatively nontoxic) is the major carrier of excess N from tissues
3
Q
Glutaminase
A
- in the kidney, intestine, and small amounts in the liver
- allows it to deaminate glutamine (arriving from the blood)
- and to eliminate the amino group as ammonium ion (NH4+) in the urine
- IRREVERSIBLE Ron
- KIDNEY glutaminase induced by chronic acidosis
- (where excretion of ammonium may become the major defense mechanism)
- High levels of Glutaminase in the intestine (where ammonium ion from deamination can be sent directly to the liver via the portal blood and used for urea synthesis)
- the intestinal bacteria and glutamine from dietary protein contribute to the intestinal ammonia entering the portal blood
4
Q
Aminotransferases (aka transaminases)
A
- in both liver and muscle
- do not release the amino groups as free ammonium
- transfer the amino group from 1 AA to another (usually alpha-ketoglutarate, a CAC intermediate)
- Pyridoxal phosphate (PLP) derived from Vitamin B6 is required to mediate the transfer
- named by the AA donating the amino group to alpha-ketoglutarate.
- Ex) alanine aminotransferase (ALT)
- Ex) aspartate aminotransferase (AST)
- in pathologic conditions may leak into blood = indicate liver or muscle damage
5
Q
Glutamate Dehydrogenase
A
- found in many tissues
- REVERSIBLY deaminates Glutamate
- produces alpha-ketoglutarate (CAC intermediate)
6
Q
What is the major carrier of excess N from tissues
A
- Glutamine (relatively nontoxic)
- most tissues add excess N to the blood as glutamine by attaching ammonia to the gamma-carboxyl group of glutamate
- Muscle sends N to the liver as alanine and smaller # of other aa including glutamine
7
Q
What are the sources of N for the urea cycle?
A
NH3 and aspartate
8
Q
Urea cycle
A
- urea contains 2 N and is synthesized in the liver from aspartate and carbamoyl P
- carbamoyl P: made from ammonium ion (NH4+) and CO by mito carbamoyl phosphate synthase (requires N-acetylglutamate as an activator)
- N-acetylglutamate is only produced when free AA are present
- rate-limiting enzyme: mito carbamoyl phosphate synthase
- acts catalytically
- small # of the intermediates can synthesize large # of urea
- occurs partially in the mito and partially in the cytoplasm
- citrulline enters cytoplasm and ornithine returns to the mitochondria (mitochondrial ornithine transcarbamoylase)
9
Q
if gluconeogenesis is active, fumarate can be converted to
A
glucose
10
Q
the product of the urea cycle (urea) is formed in the
A
cytoplasm and enters the blood of delivery to the kidney
11
Q
Carbamoyl Phosphate Synthetase Deficiency
- remember, this is a mitochondrial enzyme
A
- increased [NH4+]; hyperammonemia
- increased blood glutamine
- decreased BUN
- No orotic aciduria* (excretion of orotic acid in urine)
- AR*
- cerebral edema (lethargy, convulsions, coma, death)
12
Q
Ornithine Transcarbamoylase Deficiency
- remember, this is a mitochondrial enzyme
A
- increased [NH4+]; hyperammonemia
- increased blood glutamine
- decreased BUN
- orotic aciduria** (excretion of orotic acid in urine)
- X-Linked Recessive**
- cerebral edema (lethargy, convulsions, coma, death)
- Without OTC, Carbamoyl P accumulates in mito and leaks into the cytoplasm
- Carmaboyl P is first substrate in pathway of orotic acid metabolism
13
Q
Phenylalanine Hydroxylase Deficiency (Phenylketonuria aka PKU)
A
- 1:15,000
- normal at birth. If untreated: slow development,
- severe mental retardation, autistic symptoms
- loss of motor control
- musty odor to urine bc there’s an increase in phenyl-ketones
- kids have pale skin and white-blonde hair
- sx from high levels pf he and not to the phenylketones. Tx: diet LOW in phe (but still need some bc essential AA)
- avoid aspartame
- diet important during pregnancy: infants born to PKU mothers have microcephaly, mental retardation and low birth weight
- screen infants a couple days after birth
14
Q
MCC elevated BUN
A
dehydration
15
Q
Transaminases use what as a coenzyme?
A
- Vitamin B6 aka pyridoxine
16
Q
Seeing alanine in the blood is a sign of
A
starvation
17
Q
IF BUN is too high
A
kidney dysfunction
18
Q
if BUN is too low
A
liver dysfunction
19
Q
What causes Parkinson’s Diasease?
A
- loss of dopamine producing cells in the brain
- catecholamines (Dopamine) don’t enter the brain, brain synthesizes them locally
- L-dopa can cross the BBB
- Sx: bradykinesia
- mask-like facies
- pill rolling, RESTING tremor
- cogwheel rigidity
20
Q
Homogentisate Oxidate Deficiency
A
- causes alcaptonuria
- accumulation of homogentistic acid in the blood
- causes excretion in urine, which darkens when exposed to air
- Dark pigment also accumulates over years in cartilage (ochronosis)
- and may be seen in the sclera of the eye, in ear cartilage
- puts develop arthritis in adulthood, usually in 3rd decade
- Sx not present in all patients w enzyme deficiency
21
Q
Branched Chain Ketoacid Dehydrogenase Deficiency
A
- Maple Syrup Urine Disease
- BCKDH metabolizes branched-chain ketoacids produced from their cognate AA: valine, leucine and isoleucine)
- infants normal for the first few days of life
- progressive lethargy, weight loss
- alternating episodes of hypertonia and hypotonia
- urine develops a maple syrup odor
- ketosis, coma and death if not treated
- tx: restrict dietary valine, leucine and isoleucine
- Branched Chain Ketoacid Dehydrogenase is similar to alpha-ketoglutarate dehydrogenase (both are TLCFN enzymes) “Tender Loving Care For Nancy” Requires:
T: Thiamine
L: lipoic acid
C: CoA
F: FAD
N: NAD+
22
Q
Propionyl-CoA Carboxylase Deficiency
A
- accumulation of propionic acid, methyl citrate, hydroxypropionic acid
- valine, methionine, isoleucine and threonine are all metabolized through the propionic acid pathway (used for all odd-C FA)
- deficiency of either Propionyl-CoA Carboxylase or methylmalonyl-CoA Mutase results in
- neonatal ketosis from failure to metabolize ketoacids produced from these 4 AA
- the presence of methyl citrate and hydroxypropionate distinguish PCoA CD from MMCoA MD
23
Q
When a biochemical reaction requires a methyl group (methylation) what is the usual methyl donor?
A
S-adenosylmethionine (SAM)
24
Q
Alcaptonuria
A
- Homogentisate Oxidate Deficiency
- accumulation of homogentistic acid in the blood
- causes excretion in urine, which darkens when exposed to air
- Dark pigment also accumulates over years in cartilage (ochronosis)
- and may be seen in the sclera of the eye, in ear cartilage
- puts develop arthritis in adulthood, usually in 3rd decade
- Sx not present in all patients w enzyme deficiency
25
Q
Maple Syrup Urine Disease
A
- Branched Chain Ketoacid Dehydrogenase Deficiency
- BCKDH metabolizes branched-chain ketoacids produced from their cognate AA: valine, leucine and isoleucine)
- infants normal for the first few days of life
- progressive lethargy, weight loss
- alternating episodes of hypertonia and hypotonia
- urine develops a maple syrup odor
- ketosis, coma and death if not treated
- tx: restrict dietary valine, leucine and isoleucine
- Branched Chain Ketoacid Dehydrogenase is similar to alpha-ketoglutarate dehydrogenase (both are TLCFN enzymes) “Tender Loving Care For Nancy” Requires:
T: Thiamine
L: lipoic acid
C: CoA
F: FAD
N: NAD+
26
Q
How are valine, methionine, isoleucine and threonine are metabolized?
A
- valine, methionine, isoleucine and threonine are all metabolized through the propionic acid pathway (used for all odd-C FA)
- deficiency of either Propionyl-CoA Carboxylase or methylmalonyl-CoA Mutase results in
- neonatal ketosis from failure to metabolize ketoacids produced from these 4 AA
- Distinguish btw the 2 enzyme deficiencies by:
- presence of methyl citrate and hydroxypropionic acid in propionyl CoA carboxylase deficiency
- presence of methylmalonic aciduria (results from accumulation of methylmalonic acid) in methylmalonyl CoA mutase deficiency
