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Flashcards in AA Metabolism (Biochem) Deck (65)
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1

How does the body get rid of excess N

- 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

Glutamine Synthetase

- 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

Glutaminase

- 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

Aminotransferases (aka transaminases)

- 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

Glutamate Dehydrogenase

- found in many tissues
- REVERSIBLY deaminates Glutamate
- produces alpha-ketoglutarate (CAC intermediate)

6

What is the major carrier of excess N from tissues

- 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

What are the sources of N for the urea cycle?

NH3 and aspartate

8

Urea cycle

- 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

if gluconeogenesis is active, fumarate can be converted to

glucose

10

the product of the urea cycle (urea) is formed in the

cytoplasm and enters the blood of delivery to the kidney

11

Carbamoyl Phosphate Synthetase Deficiency

* remember, this is a mitochondrial enzyme

- 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

Ornithine Transcarbamoylase Deficiency

* remember, this is a mitochondrial enzyme

- 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

Phenylalanine Hydroxylase Deficiency (Phenylketonuria aka PKU)

- 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

MCC elevated BUN

dehydration

15

Transaminases use what as a coenzyme?

- Vitamin B6 aka pyridoxine

16

Seeing alanine in the blood is a sign of

starvation

17

IF BUN is too high

kidney dysfunction

18

if BUN is too low

liver dysfunction

19

What causes Parkinson's Diasease?

- 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

Homogentisate Oxidate Deficiency

- 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

Branched Chain Ketoacid Dehydrogenase Deficiency

- 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

Propionyl-CoA Carboxylase Deficiency

- 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

When a biochemical reaction requires a methyl group (methylation) what is the usual methyl donor?

S-adenosylmethionine (SAM)

24

Alcaptonuria

- 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

Maple Syrup Urine Disease

- 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

How are valine, methionine, isoleucine and threonine are metabolized?

- 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

27

Methylmalonyl-CoA Mutase Deficiency

- accumulation of methylmalonic 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
- results in methylmalonic aciduria
- presence of methylmalonic aciduria distinguishes MM-CoA MD from P-CoA CD

28

Homocystinuria

- can be caused (rarely) by cystathionine synthase deficiency (Vit B6 cofactor)
- methionine accumulates in blood (bc CS converts homocysteine to cystathionine; but when CS is missing, homocysteine is converted to methionine via homocysteine methyl transferase (VB12 cofactor))
- atherosclerosis (can cause stroke)
- DVT, thromboembolism
- dislocation of lens downward and inward* (ectopic lens)
- marfan-like habitus (may see abnormally long "spidery" fingers)
- mental retardation
- joint contractures
- excrete high-levels of homocysteine in urine (dx with cyanide-nitroprusside test)
- often have MI before 20 yo
- Tx: diet low in methionine and supplement folate and vitamin B6
- many patients with homocystinuria who have partial activity of CS respond well to pyridoxine administration
* in Marfan, subluxation of the lens is upward and outward

29

homocystinemia from vitamin deficiencies

- caused by:
- folate deficiency
- Vitamin B12 (required for homocysteine methyl transferase activity)
- Vitamin B6 (required for cystathionine synthase deficiency)
- assoc with increased risk of atherosclerosis, DVT, stroke

30

Branched Chain Ketoacid Dehydrogenase

- metabolizes branched-chain ketoacids produced from their cognate AA: valine, leucine and isoleucine)
- TLCFN enzyme. Requires:
T: Thiamine
L: lipoic acid
C: CoA
F: FAD
N: NAD+
- "Tender Loving Care For Nancy"
- similar to alpha-ketoglutarate dehydrogenase (also requires TLCFN)