Erythrocyte Biochemistray (Pt. 2) Flashcards
What is the general structure of heme?
- heterocyclic porphyrin ring
- iron in the center
In heme, what state is the iron?
ferrous (Fe2+)
Where in the body is heme synthesized?
liver
erythroid cells of bone marrow
In what part of the cell does Phase I of heme synthesis occur?
mitochondria
What reaction constitutes Phase I of heme synthesis?
glycine + succinyl CoA
(via ALA synthase req. B6) =
aminolevulinic acid
*rate-limiting step
What is the rate-limiting step of heme synthesis?
ALA synthase
synthesis of aminolevulinic acid
What vitamin cofactor is needed by ALA synthase?
B6
In what part of the cell does Phase II of heme synthesis occur?
cytosol
What is the first step in Phase II of heme synthesis?
ALA + ALA
(via ALA dyhydratase) =
porphobilinogen (PBG)
What three enzymes are utilized in Phase II of heme synthesis?
porphobilinogen deaminase
uroporphyrinogen III synthase
uroporphyrinogen decarboxylase
What is the final product of Phase II in heme synthesis?
coproporphyrinogen III
Where in the cell does Phase III of heme synthesis occur?
mitochondria
What enzyme in Stage III of heme synthesis, if deficient, is responsible for variegate porphyria?
protoporphyrinogen IX oxidase
changes protoporphyrinogen to protoporphyrin IX
What enzyme changes protoporphyrin IX to heme?
ferrochelatase
What two enzymes in heme synthesis are inhibited by lead?
aminolevulinic acid dehydratase
ferrochelatase
What important biological substance, other than hemoglobin, contains heme?
cytochromes
In lead poisoning, which intermediate of heme synthesis accumulates and becomes neurotoxic?
aminolevulinic acid
What are the types of symptoms exhibited by acute hepatic porphyrias?
neurologic symptoms
What are the types of symptoms exhibited by erythropoietic porphyrias?
skin
photosensitivity
What enzyme deficiency causes acute intermittent porphyria?
porphobilinogen (PBG) deaminase
-in the liver
What are the characteristics of acute intermittent porphyria?
- buildup of porphobilinogen (PBG)
- autosomal dominant
- periodic attacks of abdominal pain
- periodic neuro dysfunction
- type: hepatic
What enzyme deficiency causes congenital erythropoietic porphyria?
uroporphyrinogen III synthase
-in erythrocytes
What are the characteristics of congenital erythropoietic porphyria?
-buildup of uroporphyrinogen I and its oxidative products
- autosomal recessive
- red-colored teeth and urine
type: erythropoietic
What enzyme deficiency causes porphyria cutanea tarda?
uroporphyrinogen III decarboxylase
What are the characteristics of porphyria cutanea tarda?
- buildup of uroporphyrinogen III and uroporphyrinogen I
- autosomal dominant (most common porphyria in U.S.)
- photosensitivity, wine-colored urine
- type: hepatoerythropoietic
What enzyme deficiency causes variegate porphyria?
protoporphyrinogen IX oxidase
What are the characteristics of variegate porphyria?
buildup of porphyrinogen IX
- autosomal dominant
- photosensitivity
- neurologic symptoms
- developmental delay in children
What system degrades hemoglobin?
reticulo-endothelial system
Delineate the intermediates and enzymes from heme to bilirubin.
Heme -heme oxygenase Biliverdin -biliverdin reductase Bilirubin
What enzyme removes heme from its cyclic form into a linear form?
heme oxygenase
the 1st rxn in heme degradation
What are the characteristics of the first reaction in heme degradation, catalyzed by heme oxygenase?
- requires oxygen
- releases carbon monoxide
- iron is oxidized from ferrous to ferric form
What is needed by biliverdin reductase?
NADPH
Once bilirubin is created from the degradation of heme, what happens to it?
- released into the bloodstream
- bound to albumin
- transported to the liver
What enzyme is needed to conjugate bilirubin in the liver?
UDP-glucuronyl transferase
What other molecule is bilirubin conjugated with in the liver?
glucuronic acid
What is the rate-limiting step of heme degradation?
conjugation of bilirubin and glucuronic acid
via UDP-glucuronyl transferase
After conjugation, where does the bilirubin-diglucuronide go?
- released into the gall bladder as bile
- secreted into small intestine in response to food
What happens to bilirubin-diglucuronide in the intestines?
- microbial reduction to urobilinogen
- further microbial reduction to stercobilin
What happens to the portion of the urobilinogen that gets reabsorbed from the intestines?
it gets processed by the kidneys
-becomes urobilin
What are normal levels of unconjugated and conjugated bilirubin in the body?
- 2-0.9 mg/dL (unconjugated)
0. 1-0.3 mg/dL (conjugated)
What are some characteristics of pre-hepatic jaundice?
- increased production of unconjugated bilirubin
- excess hemolysis
- capacity of liver to uptake BR is exceeded
- Ex: internal hemorrhage, mom-baby blood group
What would be the lab findings of a pt with pre-hepatic jaundice?
- increased blood levels of unconjugated bilirubin
- normal blood levels of conjugated bilirubin
- normal liver enzymes
- urobilinogen present in the urine
What are some characteristics of intra-hepatic jaundice?
-impaired hepatic uptake of unconjugated bilirubin, conjugation, or secretion of conjugated bilirubin
- generalized hepatic dysfunction
ex: cirrhosis, Criggler-Najjar or Gilbert Syndromes
What would be the lab findings of a pt with intra-hepatic jaundice?
-varying increases in unconjugated and conjugated bilirubin (depending on the cause)
- increase in other liver markers and enzymes
- normal urobilinogen levels in urine
What are some characteristics of post-hepatic jaundice (aka Cholestatic Jaundice or Cholestasis)?
- decreased bile flow
- problems with bilirubin secretion
- ex: obstruction, gall stones, tumors, drugs
What would be the lab findings of a pt with intra-hepatic jaundice?
-elevated blood levels of conjugated bilirubin
-small increases in unconjugated bilirubin
(d/t bilirubin backing up)
-normal liver enzymes
-elevated alkaline phosphatase
Why would a pt with post-hepatic jaundice have dark-colored urine?
- conjugated bilirubin is present in the urine
- no urobilinogen in the urine
-conjugated BR couldn’t get into the gut, so the liver released it back out into the bloodstream
Why would a pt with post-hepatic jaundice have light-colored and pale stool?
- no stercobilin in the feces
- conjugated BR couldn’t get into the gut, so the liver released it back out into the bloodstream
What are some characteristics of Neonatal Jaundice?
- physiological jaundice
- immature hepatic metabolic pathways
- -deficiency of UDP-glucuronyl transferase
- breakdown of fetal Hb as it’s replaced by adult Hb
How does phototherapy aid in treating jaundice?
-blue fluorescent light causes bilirubin to change into more soluble isomers
Besides phototherapy, what is another treatment for jaundice and what is its mechanism of action?
- intramuscular injection of tin-mesoporphyrin
- inhibition of heme oxygenase
What is Criggler-Najjar Syndrome?
- absence of or 90 percent diminshed activity of UDP-glucuronyl transferase
- severe hyperbilirubinemia; BR accumulates in baby’s brain … encephalopathy and brain damage
What are possible treatments for Criggler-Najjar Syndrome?
- blood transfusions and phototherapy
- hemo oxygenase inhibitors
- oral calcium phosphate and carbonate (forms complexes with BR in the GI tract)
- liver transplant before brain damage occurs
What is Gilbert Syndrome?
- benign disorder (2-10% of the population)
- reduced UDP-glucuronyl transferase activity (25 percent)
-bilirubin may increase with fasting, stress, or alcohol consumption
What is hepatitis?
- inflammation of the liver, leading to liver dysfunction
- bilirubin accumulates in skin and sclera of the eyes
- causes: viral infection (A, B, C), alcoholic cirrhosis, liver cancer
What are the lab findings of a patient with hepatitis?
elevated levels of unconjugated and conjugated bilirubin
-dark, tea-colored urine
