Heme Metabolism

What is heme composed of

Iron (Fe 2+) and protoporphyrin

What is a porphyrin

The family of molecules with 4 pyrrole rings that heme is part of. Porphyrins are able to stably complex with metal ions.

What is a pyrrole

What is hemin?

Fe3+ oxidation product of heme

where is heme found?

Found in hemoglobin and myoglobin
CYP-450
Enzymes (catalase)

What are the heme side chains?

Pyrrole, Methyl, Vinyl, Propionate

What connects the pyrroles?

Methine bridges

Where is heme synthesized from for erythrocytes

Bone marrow acid pool

Where is heme synthesized from for Cytochromes

Liver amino acid pool

Where is heme synthesized the most

Heme is synthesized the most in hemoglobin at 70% and in the cytochroms for 15%

What stimulates heme synthesis in bone marrow

EPO in the kidney cause RBC production to increase when the O2 concentration in the body is low

Cytochrome P450 heme characteristics

Built in the liver, also has a higher turn over rate

What type of Uroporphyrin does Heme use?

Urporphyrin uses Type 3

What are the main uses for porphyrin

chelate and hold the Ferrous iron in the middle. It is made from porphrinogens

ALAS 1 function

used in delta aminolevulinate synthase in the porphyrin synthesis in the Liver mitochondria

ALAS 2 function

used in d-aminolevulinate synthase in poryphrin synthesis in the bone marrow mitochondria

Hemin inhibition of Cyt P450

decreases the expression of ASLAS1 in the liver via feedback inhibition

What inhibits ALAS 2

Low iron will inhbit ALAS 2 in the bone marrow/ erythroid cells

What does Phenobarbital, griseofulvin, or hydantoins do to cyt P 450

It increases it the Cyt P450 which will increase ALAS1 production due to increased cunsumption of heme in the liver which will cause a bild up of protophoryin in the liver and cause Cirrhosis

What regulates ALAS 2

Availability of iron regulates ALAS2. if there isnt enough Ferrous iron in the bone marrow the body wills top producing ALAS2 so that there isnt just extra iron free prophyrins laying around.

Also EPO regulates it as well

X linked sideroblastic anemia

Deficiency in ALAS2 enzyme which makes abailable iron unusable to create heme

Porphyrin synthesis steps

1. 2 ALA condensed to porphobilinogen via ALA dehydratase

- Create the side chains!!!!

2. add 4 NH3 to make Hydroxymethylbilane

3. Close the ring to make uroporphyrinogen 3

4. Decarboxy it and make Coproporphyrinogen 3

5. Push it to mtochondria

6. Oxidate it to Protoporphyrin

7. use Ferrochelatase to ass FE2+ making it Heme Protoporphyrin (ie Heme)

What is ferrochelatase

Ferrochelatase is a mitochondrial enzyme involved in the last step of heme synthesis wherein iron is incorporated into the protoporphyrin ring.

Which phases of porphyrin synthesis occour in the mitochondria?

Step 1: Making Delta Aminlevulinic acid first occours in the mitochondria but then is pushed to the cytosol

Step 5: Pushing the coprophyrinogen into the mitochondria

Step 6: oxidation to Protoporphyrin

and adding the derrochelatase Ferrous iron

What are porphyrias

rare disorders associated with heme synthesis which result in an inability to form heme and a build up of precursor molecules

occour w/ lead poisioning

primarily autosomal dominant or acquired enzyme deficiencies

Symptoms of porphyrias

Erythropoietic - photosensitivity (Tetrapyrroles) and dermatitis
Hepatic- Neurological (Neurotoxity)
Abdominal - Accumulating metabolic intermediates
Mixed - photosensitivity, dermatitis, and neurological

porphyria Cutanea Tarda

photosensitive bullous disease; deficiency uroporphyrinogen decarboxylase

-Hepatic chronic

ALA dehydratase deficiency

Lead poisoning
- Block Protoporphyrin from turning to heme

Acute intermittent porphyria

Cause Delta ALA to get backed up and no photosensitivity
- Liver

Congenital erythropoietic porphyria

Stops Hydroxy from going to Uroporphy 3
- Erythro Bone

- Cause uro 1 and coporo 1 to build up in urine

Porphyria cutanea tarda (PCT)

Stops Uroporphy 3 from going to coporo 3 in cytosol
- most common
- uroporo 3 in urine
- Deficiency in Uropropo decarby
-shows skin eruptions and pink urine

What influences PCT

iron, sunlight, alcohol, hepatitis, HIV and estrgen

What is the ultimate result of porphyrias

decrease in heme synthesis since ALAS can finish its process to create heme

Acute hepatic porphyrias

Common characteristics:
Acute attacks of vomiting & pain
Neurological/psychiatric problems

- Build up of ALA, this can also be due to drug intake causing Cyt P 450 demand to increase making overproduction

How does Acute hepatic porphyrias increase w drug metabolism

Intake of drugs increae Cyt P 450 demand for heme due to drug metabolism. this increases ALA and then can cause an accumulation in the urine of metabolites of ALA

Erythropoietic porphyrias

accumulation of porphyrin in BM associated with increased blister and rashes in early child hood possibilioty for cirrhosis

Heme degredation process

Old RBCs eatent by macrophages

Heme -> bilirubin

Bilirubin jumps onto albumin goes to liver

Liver conjucgates bili send to bile then intestine

Intestine deconjugates bili -> Urobilinogen
- Some goes to feces brown some goes to kidney

Urobolinogen goes to kidney -> urobilin (yellow)

What does heme oxygenase do?

converts heme to biliverdin, by releasing Fe 3+ and preaks the Protoporphyrin ring

What does Biliverdin reductase do?

converts biliverdin to bilirubin to be carried on albumin to the liver to become conjugated

What does it mean to conjugate bilirubin?

add UDP glucuronide making it bilirubin diglucuronide so it can go to the bile

What are normal serum bilirubin levels and when does jaundice occour

2-17mM
Jaundice occours at 40 mM

What is Prehepatic Jaundice and what is it a symptom of?

Result of excessive destruction of red blood cells
-Impaired liver uptake
Characteristic of hemolytic anemias/Thalassemia/transfusion reactions

What is hepatic jaundice and what does it come from

decrease in conjugation so it just stays a bilirubin in the system
Jaundice resulting from Hepatitis, Cirrhosis, Cancer, drugs

what causes Post hepatic jaundice

Blocked bile duct
-Issues w excretion
-galls tones

What is neonatal jaundice

-messed up bilirubin UDP glucuronyl transferase
- Treat w phototherapy

What is unconjugated hyperbilirubinemias

Caused by hemolysis, UDP glucoronidate issues which happens before entering the liver.

What is Gilbert syndrome

Liver struggles process billirubin so slight increase in unconjugated bili

Crigler-Najjar syndrome

Absolutely no conjugated bili, UDP Gluco transferase is broken

What is kernicterus?

brain dysfunction in babies due to bili conjugation issues

What enzyme conjugates bilirubin

Uridine Glucuronyl Transferase(UGT) in hepatocytes.

What is Dubin-Johnson syndrome (Conjugated)?

Inability to secrete conjugated bili to the bile

What is rotor syndrome

Conjugated bili secretes/ leaks into the blood stream causing hyperbilirubinemia due to messed up hepatocellular storage