Biochem Exam 5: Heme Synthesis & Degradation

Front 1

Heme consists of a ______________ ring w/ an iron atom in the center.
In complex w/ proteins it forms what?

Back 1

porphyrin

hemoproteins

Front 2

Hemoproteins __________ & ____________ are involved in oxygen transport.
______________ is envolved in catalysis & electron transport.

Back 2

hemoglobin & myoglobin

cytochromes

Front 3

What is the rate limiting step in heme synthesis?

Where does this occur?

Back 3

step 1: Succinyl CoA + glycine to delta-ALA
via delta-aminolevulinic acid synthase (ALAS)
with coenzyme pyridoxal phosphate

in mitochondria

*Succinyl CoA from TCA

Front 4

How is the rate limiting step regulated?

Back 4

-heme (final product) allosterically inhibits ALAS (neg feedback)
-low iron inhibits transcription of ALAS
-heme also inhibits synthesis

Front 5

What are the 2 forms of ALAS?

Back 5

1. Erythroid-specific
-expressed in RBC precursors
-gene ALAS2 on X chromosome
-expressed only during active heme synthesis
-regulated by iron

2. Ubiquitous
-gene ALAS1 on chromosome 3

Front 6

A mutation in what gene can lead to X-linked sideroblastic anemia?
how is it treated?

Back 6

ALAS2
TX: pyridoxine (ALAS cofactor)
sideroblasts are abnormal nucleated erythroblasts

Front 7

What is a sideroblast?

Back 7

an abnormal nucleated erythroblast

Front 8

What steps of heme synthesis occur in the cytoplasm?

Back 8

steps 2-5

*1 & 6-8 occur in mitochondria

Front 9

Name the Poryphyrias that include photosensitivity as a symptom, what enzyme are each deficient in?

Back 9

steps 4-8
4. congenital erythropoietic porphyria (uroporphyrinogen III cosynthase)
5. porphyria cutanea tarda
(uroporphyrinogen decarboxylase)
6. hereditary coproporyphyria
(coproporphyrinogen oxidase)
7. veriegate porphyria
(protoporphyrinogen oxidase)
8. erythropoietic protoporphyria
(ferrochelatase)

Front 10

What Rx can tx prophyria and how?

Back 10

Hematin or heme aginate can allosterically inhibit ALA synthase thus decreasing heme synthesis.

Front 11

How do many drugs result in increased ALAS activity?

Back 11

-drugs are metabolized by Cyt P450 monooxygenase system
-require increased Cyt P450
-leads to increased consumption of heme
-results in increased synthesis of ALAS

Front 12

What is the 2nd step in heme synthesis?

Back 12

2 molecules of delta- ALA --->Porphobilinogen
via delta-ALA dehydratase

Front 13

What toxin can interfere with the synthesis of heme and how?

Back 13

Lead can inhibit ALA dehydratase and ferrochetalase leading to anemia.

*coproporphyrin III & ALA will accumulate in urine

Front 14

What enzyme is involved in introducing Fe to protoporphrin IX (final step)? What pathology is assoc. with it?

Back 14

Ferrochetalase (increases rx rate, will still occur w/o).

Erythropoetic protoporphyria (autosomal recessive).

Front 15

What is the affected enzyme, accumulated product and symptoms in X linked dominant protoporphyria?

Back 15

ALA synthase. (gain of function mutation in ALAS2 gene)
Free and Zn protoporphyrin IX.
Photosensitivity and liver damage.

Front 16

Porphyrias are autosomal dominant disorders, except for 3 exceptions, what are they?

Back 16

ALA dehydratase porphyria (recessive)

Congenital erythropoetic porphyria (recessive)

X-linked dominant protoporphyria (X-linked)

Front 17

What RBC enzymes are deficient in ALA dehydratase prophyria & congenital erythripoietic porphyria?

Back 17

ALA dehydratase prophyria: ALA dehydratase

Congenital erythripoietic porphyria: uroporphyrinogen III synthase

Front 18

What is the affected enzyme, accumulated product and symptoms in acute intermittent prophyria?

Back 18

Hydroxymethlbilane synthase.
Prophobilinogen and delta ALA.
Abd pain, N/V. (Liver)

Front 19

What is the affected enzyme, accumulated product and symptoms in Porphyria cutanea tarda (PCT)?

Back 19

Uroporphyrogen decarboxylase.
Uroporphyrin in urine.
Photosensitivity. (Liver and bone marrow)

*most common subtype of porphyria
*blisters on skin exposure to light, red urine

Front 20

What is the affected enzyme, accumulated product and symptoms in hereditary corpoporphyria?

Back 20

Corporphyrinogen oxidase.
Corpoporphyrinogen III (& others before block in urine)
Photosensitivity, N/V. (Liver)

Front 21

What is the affected enzyme, accumulated product and symptoms in erythropoetic protoporphyria?

Back 21

Ferrochelatase.
Protoporphyrin in RBCs, marrow and plasma. Photosensitivity.

Front 22

What is the affected enzyme, accumulated product and symptoms varigate porphyria?

Back 22

Protoporphyrinogen oxidase.
Protoporphyrin IX.
Photosensitive (liver).

Front 23

Hyperbilirubinemia-
What is the affected enzyme and accumulated product in Gilbert's syndrome?

Back 23

-25-30% reduction in glucuronyl transferase.
(autosomal recessive- promotor region mutation)
(autosomal dominant- missense UGT1A1 gene)
-Unconj. bili. accumulates
-Pt may be asymptomatic.

Front 24

Hyperbilirubinemia-
What is the affected enzyme, accumulated product and symptoms in Cringer-Najjar syndrome?

Back 24

-def. in glucuronyl transferase. (more severe than GIlbert)
(autosomal recessive- mutation in both UGT1A1)
-severe unconj. hyperbili accum (above 375umol/L)
-Can cause kernicterus in neonates, fatal if enzyme completely absent
-treat w/ UV light, liver transplant
*amish & mennonites

Front 25

Hyperbilirubinemia-
What is the affected enzyme, accumulated product and symptoms in Dublin-Johnson syndrome?

Back 25

-Impaired biliary secretion of conj. bili.
Mutation in (ABC) organic anion transporter.
-conj bilirubin accum
-Black pigmentation of liver.

Front 26

Hyperbilirubinemia-
What is the affected enzyme, accumulated product and symptoms in Rotor syndrome?

Back 26

-Impaired biliary secretion of conj. bili.
(Exact enzyme unknown)
-conj bilirubin accumulated
-NO Black pigmentation of liver!

*extremely rare

Front 27

What are the causes/effects of prehepatic jaundice?

Back 27

cause: excessive hemolysis

effect: absent conjugated bilirubin & urine bilirubin, present urine urobilinogen

Front 28

What are the causes/effects of intrahepatic jaundice?

Back 28

cause: impaired uptake, conjugation, or secretion of bilirubin (virus, toxins, genetic errors)

effect: increased conjugated bilirubin, increased AST & ALT, present urine bilirubin & urobilinogen
*accompanied w/ other liver problems

Front 29

What are the causes/effects of posthepatic jaundice?

Back 29

cause: bile duct blockage (gallstones, etc)

effect: increased conjugated bilirubin, increased ALP, present urine bilirubin, absent urine urobilinogen

Front 30

What are the causes of neonatal jaundice?

Back 30

-combination of excessive intravascular hemolysis & underdeveloped liver (bilirubin conjugation enzymes deficienct)

Front 31

How does phototherapy treat jaundice?

Back 31

converts bilirubin to isomers; lumirubin or isolumirubin, that can be removed from body w/o conjugation

Front 32

What is the difference btwn erythropoetic & hepatic porphyrias?

Back 32

erythropoeitc:
-def bone marrow enzyme
-chronic

hepatic:
-def liver enzyme
-acute & chronic

Front 33

In general, porphyrias cause ______________
& can be treated with ________________

Back 33

-increased synthesis of ALAS
-treat w/ IV injection of hemin

Front 34

What are the causes/types of hyperbilirubinemia?

Back 34

> 3mg/dL bilirubin---> jaundice

1. unconjugated: insufficient conjugation, excessive hemolysis
2. conjugated: less severe

Front 35

How does Phenobarbital treat neonatal jaundice when administered to mother prior to birth?

Back 35

induces fetal synthesis of UDP glucuronyl transferase
(necessary to conj. bilirubin)

*camel milk can also treat jaundice*

Front 36

Van der Bergh reaction is used to measure conjugated bilirubin (direct/indirect)
What should normal levels be?

Back 36

direct bilirubin
normal: 0-0.4 mg/dL

Front 37

How is total bilirubin measured?
Thus uncongucated bilirubin can be calculated (direct?indirect)
What are normal levels?

Back 37

by addition of alcohol

indirect measure unconj. bilirubin
normal_ 0.1-1 mg/dL

Front 38

Untreated neonatal jaundice can lead to what?

Back 38

kernicterus

Front 39

Sites & major steps in heme degradation & bilirubin production

Back 39

1. Globulin is removed from hemoglobin --> heme
2. Heme ---> biliverdin (via heme oxygenase)
3. Biliverdin ---> bilirubin (via biliverdin reductase)

Front 40

What are the major sources of bilirubin?

Back 40

85% RBC breakdown
15% other heme-containing enzymes

Front 41

Normally RBCs are degraded ______________, but lysis can also occur ______________ (in blood stream)

Back 41

extravascularly
intravascularly

Front 42

How is unconjugated bilirubin transported to the liver?

Back 42

in complex w/ albumin

Front 43

Steps of bilirubin metabolism w/i Hepatocyte:

Back 43

1. bilirubin-albumin complex trasnferred into hepatocyte & bilirubin released
2. ligandins transport bilirubin to ER w/i hepatocyte
3. bilirubin + glucuronic acid ---> bilirubin diglucuronide (via glucuronyltransferase)

Front 44

Why does bilirubin need to be conjugated to bilirubin diglucuronide?

Back 44

makes it more polar & water soluble, allowing it to be secreted into bile

Front 45

What does free hemoglobin do?

Back 45

-scavenge iron
-prevents major iron loss
-complex w/free heme

Front 46

What do haptoglobin & hemopexin bind?

Back 46

haptoglobin- binds hemoglobin
-metabolized in liver & spleen, forms iron-globulin complex & bilirubin
-prevents loss or iron in urine

hemopexin- binds free heme
-complex taken up in liver
-iron stored bound to ferritin

Front 47

Where is conjugated bilirubin converted to urobilinogen? stercobilin?

Back 47

urobilinogen, by bacteria in gut (colorless)

stercobilin, excreted in feces (colored)