AA Metabolism (Biochem) Flashcards Preview

Kaplan Biochem and Genetics > AA Metabolism (Biochem) > Flashcards

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

31

Subluxation of lens in Marfans vs cystathionine synthase deficiency

- Marfan: subluxation up and down
- cystathionine synthase deficiency: subluxation down and in

32

in homocystinuria what reactions are impaired

- can be caused (rarely) by cystathionine synthase deficiency (Vit B6 cofactor)
- bc CS converts homocysteine to cystathionine
- but when CS is missing
- homocysteine is converted to methionine via homocysteine methyl transferase (VB12 cofactor, THF cofactor)
- methionine accumulates in blood
- thus, Vitamins B6 and B12 deficiencies can also be causes of homocystinuria
- folate deficiency can also cause homocystinuria and THF is a C donor for homocysteine methyl transferase (methionine synthesis)

33

If a 1C unit in antoher oxidation state is required (i.e. methylene, methyl, formyl)

- tetrahydrofolate (THF) serves as its donor
- ie cofactor in homocysteine methyl transferase activity, which converts homocysteine to methionine

34

branched chain ketoacids are produced from

- produced from their cognate AA
- valine, leucine and isoleucine

35

Tetrahydrofolate

- formed from the vitamin folate through 2 reductions (same reaction occurs 2x: Folate to DHF and DHF to TFH)
- catalyzed by dihydrofolate (DFH) reductase
- Folate needed for:
1. homocysteine metabolism
2. DNA synthesis
- DEFICIENCY: megaloblastic anemia results from insufficient active THF to support cell division the BM
- methotrexate inhibits DHF reductase = used as antineoplastic drug
- if VB12 deficient, methyl THF is stuck in the storage form (reduced folate = inactive = storage).
- This can be overcome with folate.
- but if have megaloblastic anemia and you're NOT making DNA, you know it's caused by folate deficiency

36

Folate Deficiency

- megaloblastic, macrocytic (MCV greater than 100) anemia
- PMN nucleus m ore than 5 lobes
- homocysteinemia with risk for CV disease
- deficiency develops in 3-4 months
- risk factors:
- pregnancy* (fetus may develop neural tube defects)
- alcoholism
- severe malnutrition
*women of childbearing age should supplement with 400-800 mg of folic acid/day
- if VB12 deficient, methyl THF is stuck in the storage form (reduced folate = inactive = storage).
- This can be overcome with folate.
- but if have megaloblastic anemia and you're NOT making DNA, you know it's caused by folate deficiency

37

k

k

38

Vitamin B12 deficiency

- Vitamin B12 aka cobalamin
- MCC = pernicious anemia (failure to absorb B12 in the absence of intrinsic factor from parietal cells)
- megaloblastic, macrocytic (MCV greater than 100) anemia
- PMN nucleus m ore than 5 lobes
- homocysteinemia with risk for CV disease
- deficiency develops in years (bc excess stored in body)
- methylmalnoic aciduria (MMA in urine)
- progressive peripheral neuropathy (not corrected by giving folate)
- risk factors:
- pernicious anemia (failure to absorb B12 in the absence of intrinsic factor from parietal cells)
- gastric resection (affects B12 absorption, so need supplements)
- chronic pancreatitis
- severe malnutrition
- vegan
- infection with D. Latum (parasite found in raw fish)
- VB12 absorption also decreases with age and in individuals with chronic pancreatitis
- can crease a 2dary deficiency of active THF
- if VB12 deficient, methyl THF is stuck in the storage form (reduced folate = inactive = storage).
- This can be overcome with folate, and corrects megaloblastic anemia

39

What enzymes require Vitamin B12?

- methylmalonyl CoA mutase
- homocysteine methyltransferase

40

Tyrosine (AA) is used to produce

- thyroid hormones T3, T4
- melanin
- catecholamines

41

Tryptophan (AA) is used to produce

- serotnonin
- NAD, NADP

42

Arginine (AA) is used to produce

NO

43

pernicious anemia

- pernicious anemia = failure to absorb B12 in the absence of intrinsic factor from parietal cells
- Vitamin B12 aka cobalamin

44

Glutamate (AA) is used to produce

gamma-aminobutyric acid (GABA)

45

Histidine (AA) is used to produce

histamine

46

Where does Heme synthesis occur

- occurs in almost all tissues bc heme proteins include not only Hb and myoglobin, but
- also the cytochromes (ETC, cytochrome p450, cytochrome b5)
- also the enzymes catalase, peroxidase
- and the soluble guanylate cyclase stimulated by NO
- pathway producing heme is controlled INDEPENDENTLY in different tissues

47

Rate-limiting step of heme synthesis in the liver

- ALA synthase (found in mitochondria)
- converts glycine + succinyl-CoA to ALA
- inhibited by heme in liver

48

Acute Intermittent Porphyria

- porphobilinogen deaminase (hydroxymethylbilane synthase) deficiency
- converts PBG (porphobilinogen) to hydroxymethylbilane
- late-onset
- AD, with variable expression
- abdominal pain (often resulting in multiple laparoscopies (scars on abdomen)
- anxiety, paranoia, depression
- paralysis
- motor, sensory or autonomic neuropathy
- weakness,
- excretion of ALA and PBG during episodes
- no photosensitivity
- in severe cases, dark port-wine color to urine on standing
- episodes may be induced by hormonal changes or drugs (i.e. barbiturates)
- barbiturates are metabolized by cytochrome p450,
- so barbiturates increase cp450 synthesis, decrease heme levels
- reduction in heme lessens the repression of ALA synthase, so more porphyrin precursors are made, which exacerbates the disease

49

Porphyria cutanea tarda

- MC porphyria
- caused by deficiency of uroporphyrinogen decarboxylase (converts uroporphyrinogen-III to corproporphyrinogen III)
- Hepatocytes unable to decarboxylate uroporphyrinogen in heme synthesis
- AD, late onset
- MC symptom = photosensitivity (chronic inflammation to overt blistering and shearing of sun-exposed skin)
- beta-carotene often administered to porphyria puts with photosensitivity to reduce the production of ROS
- hyperpigmentation
- exacerbated by alcohol
- red-brown to deep-red urine (uroporphyrin accumulates, spills out of liver, enters urine)
- may be origin of Dracula myth

50

Lead poisoning

- inactivates many enzymes including ALA dehydrate and ferrochellatase
- failure of ferrocheatase to insert Fe2+ into protoporphyrin IX to form heme
- results in the non enzymatic insertion of Zn2+ to form zinc-protoporphyrin (extremely fluorescent, easily detected)
- can produce microcytic sideroblasticanemia with ringed sideroblasts in the BM
- coarse basophilic stippling in RBC
- ringed sideroblasts in BM
- Sx: coarse basophilic stippling of erythrocytes
- headache, nausea, memory loss
- abdominal pain, diarrhea (lead colic)
- lead lines in gums (increased serum iron)
- lead deposits in abdomen and epiphyses of bone seen on Xray
- neuropathy (claw hand, wrist drop)
- increased urinary ALA
- increased free RBC protoporphyrin
- lead paint; pottery glaze; batteries
- Dx: blood lead level

51

Vitamin B6 deficiency

- Vitamin B6 aka pyridoxine
- microcytic anemia
- ringed sideroblasts in BM
- decreased protoporphyrin
- decreased ALA
- increased ferritin
- increased serum iron
- MCC = isoniazid for TB

52

Hemochromatosis

- AR, 1/200 incidence
- Mutation in hephaestin
- generally seen in men over 40 and older women
- daily intestinal absorption of 2-3mg of Fe compared to the normal 1mg
- Over 20-30y, results in levels of 20-30g of Fe in the body (compared to the normal 4g)
- hemosiderin deposits found in
- liver: cirrhosis
- pancreas: diabetes
- skin: dermatitis
- joints: arthritis
- heart: arrhythmias because Fe conducts e-
- Tx: phlebotomy (body can only lose Fe through bleeding or losing epithelial cells)

53

porphobilinogen deaminase (hydroxymethylbilane synthase) deficiency

- Acute Intermittent Porphyria
- converts PBG (porphobilinogen) to hydroxymethylbilane
- late-onset
- AD, with variable expression
- abdominal pain (often resulting in multiple laparoscopies (scars on abdomen)
- anxiety, paranoia, depression
- paralysis
- motor, sensory or autonomic neuropathy
- weakness,
- excretion of ALA and PBG during episodes
- no photosensitivity
- in severe cases, dark port-wine color to standing urine (i.e. pt notices if doesn't flush toilet immediately)
- episodes may be induced by hormonal changes or drugs (i.e. barbiturates)
- barbiturates are metabolized by cytochrome p450,
- so barbiturates increase cp450, decrease heme levels
- reduction in heme lessens the repression of ALA synthase, so more porphyrin precursors are made, which exacerbates the disease

54

Iron Deficiency

- the last enzyme in heme synthesis (Ferrochelatase) introduces G32+ into the heme ring
- failure of ferrocheatase to insert Fe2+ into protoporphyrin IX to form heme
- results in the non enzymatic insertion of Zn2+ to form zinc-protoporphyrin (extremely fluorescent, easily detected)
- deficiency of Fe produces microcytic, hypochromic anemia
- Ferrochelatase is inhibited by lead
- microcytic anemia
- increased protoporphyrin
- normal ALA
- decreased ferritin
- decreased serum iron
- dietary iron insufficient to compensate for normal loss
- Fe deficiency anemia = SE of Vitamin C deficiency

55

ferroxidase

- aka ceruloplasmin, a Cu2+ protein
- oxidizes Fe2+ to Fe3+ for transport and storage

56

transferrin

carries Fe3+ in blood

57

ferritin

- oxidizes Fe2+ to Fe3+ for storage of normal acts of Fe3+ in tissues
- loss of Fe from the body accomplished by leading and shedding epithelial cells of mucosa and skin
- body has no mechanism for excreting iron, so controlling its absorption into mucosal cells is crucial
- NO OTHER NUTRIENT IS REGULATED IN THIS MANNER

58

hemosiderin

binds excess Fe3+ to prevent escape of free Fe3+ into the blood, where it's toxic

59

Bilirubin Metabolism

- subsequent to lysis of older RBC in spleen, heme released from Hb is converted to bilirubin in histiocytes
- bilirubin is not H20 soluble; transported in blood by albumin
- hepatocytes conjugate bilirubin w glucuronic acid, increasing its water solubility
- conjugated bilirubin is secreted in bile
- intestinal bacteria convert conjugated bilirubin into urobilinogen
- portion of urobilinogen further converted to bile pigments (stercobilin) and excreted in feces (makes feces red-brown)
- bile duct obstruction results in clay-colored stools
- some urobilinogen is converted to urobilin (yellow) and secreted in urine

60

jaundice

- yellow skin, whites of eyes (icterus)
- occurs when blood [bilirubin] greater than normal
- increase in unconjugated (indirect) bilirubin, conjugated (direct) bilirubin, or both
- kernicterus: accumulation of bilirubin (usually unconjugated aka indirect) in brain; may result in death
- when conjugated bilirubin increase, may be excreted in urine = urine deep yellow/red color

61

hemolytic crisis

- w severe hemolysis, more bilirubin released into blood than can be transported on albumin and conjugated in liver
- unconjugated and total bilirubin increase and may produce jaundice and kernicterus
- confirm by low Hb and elevated reticulocyte count
- Ex) hemolysis in G6PDH deficiency
- sickle cell crisis
- Rh disease of newborn

62

UDP-glucuronyl transferase deficiency

- when bilirubin conjugation is low bc of genetic/functional deficiency of glucuronyl transferase system
- unconjugated and total bilirubin increase, causes jaundice
- Ex) crigler-najjar syndromes
- gilbert syndrome
- physiologic jaundice of the newborn (enzymes may not be fully induced; esp in premies)

63

AST increases more than ALT in

alcoholic liver disease

64

Bile duct occlusion

- ie gallstone, primary biliary cirrhosis, pancreatic cancer
- prevents conjugated bilirubin from leaving liver
- conjugated bilirubin increases in blood and may also appear in urine
- light-colored stool
- jaundice

65

ALT increases more than AST in

viral hepatitis