Heme Synthesis and Breakdown

Question 1

What is Hb made of and what is at the center of each subunit?

Answer 1

It is made up of 2 alpha globins and 2 beta globins, each subunit is made up of 4 pyrrole rings (tetra pyyrole), called porphyrin ring. Iron Fe2+ (ferrous) is bound in the middle of each porphyrin ring

Question 2

Where do the different stages of the biosynthesis of heme occur?

Answer 2

Phase one: Mito
Phase two: cytosol
Phase three: Mito

Question 3

What is the first step in phase one of heme biosynthesis?

Answer 3

Glycine + Succinyl CoA forms Aminolevulinic acid (ALA) using ALA synthase and B6 (PLP)

Question 4

What is the difference between ALASynthase 1 and ALASyntahse II?

Answer 4

1 is ubiquitous and 2 is only in BM and has an iron response element in mRNA

Question 5

What happens once ALA is transported into the cytosol?

Answer 5

ALA dehydratase is used to form porphobilinogen (one pyyrole ring)

Question 6

How is porphobilinogen made into hydroxymethylbilane?

Answer 6

4 of the porphobilinogens are by porpholinogen deaminase to form hydroxymehtylbilane (4pyyrole rings= to porphyrin ring)

Question 7

How is hydroxymethylbilane made into Copro-porphyrinogenIII (2 steps)?

Answer 7

Using urophyrinogen synthase III to form Uro-porphyrinogen III and then uroporphyrinogen decarboxylase to form Copro-porphyrinogenIII

Question 8

Once copro-porphyrinogen III is transported back into the mitochondria, how does it become Heme?

Answer 8

By using copro-oxidase which forms proto-porphyrinogen IX, combined with proto-porphyrinogen IX oxidase to form proto-porphyrin IX WHICH USES FERROCHELATASE TO FORM HEME

Question 9

What does lead (from lead poisoning) inactivate, what is there a buildup of, and what disease does it cause?

Answer 9

Inactivates: ALA dehydratase and ferrochelatase
BuildUp: ALA & protoporphyrin IX
Anemia/ decrease energy production

Question 10

What is porphyrias and what are the types?

Answer 10

Inherited metabolic disorders in heme synthesis . Two types: acute hepatic (liver), erythropoietic (bone marrow)

Question 11

What is the defective enzyme and type of porphyria associated with acute intermittent porphyria?

Answer 11

E: porphoblinogen deaminase (PBG)
T: Hepatic porphyria

Question 12

What is the defective enzyme and type of porphyria associated with Congenital erythropoietic porphyria?

Answer 12

E: uroporphyrinogen III synthase
T: Erythropoietic (BM)

Question 13

What is the defective enzyme and type of porphyria associated with Porphyria cutanea tarda (PCT)?

Answer 13

E: Urophyrinogen decarboxylase
T: Hepatoerythropoietic (both liver / BM)

Question 14

What is the defective enzyme and type of porphyria associated with Variegate porphyria (celebrity deaths)?

Answer 14

E: protoporphyrinogen IX oxidase
T: hepatic

Question 15

What does congential erythropoietic porphyria cause a build up of and what is the product/side affect?

Answer 15

Causes a build up of uroporphyrinogen I and its oxidation product uroporphyrin I which is fluoroescent

Question 16

What is the first step of heme degredation? What is used and produced?

Answer 16

Heme produces Biliverdin by heme oxidase. This reaction uses O2 and produces CO and Fe3+ (ferric)

Question 17

How is biliverdin made into Bilirubin?

Answer 17

Using biliverdin reductase and NADPH (removes double bond)

Question 18

What happens to billirubin once it is released into the bloodstream as free/indirect/unconjugated BR (insoluble)?

Answer 18

Binds to albumin and transported to liver where BR is conjugated with glucuronic acid (Bilirubin Diglucuronide), now called conjugated/direct BR.

Question 19

How is UDP glucuronate made and what catalyzes the reaction between UDP glucuronate and bilirubin?

Answer 19

Made by UPD Glucose (2NAD) and UDP glucose dehydrogenase, 2 UDP glucuronate are combined with bilirubin by Bilirubin UDP glucuronyltransferase, forming Bilirubin Diglucuronide

Question 20

When newly synthesized bilirubin diglucuronide is released, where does it go and when is it released?

Answer 20

conjugated bilirubin is sent to the gull pladder which is eventually released into the small intestine in response to food

Question 21

What happens to conjugated bilirubin in the intestine?

Answer 21

The diglucuronides are removed and bilirubin is reduced to urobilinogen

Question 22

What happens when the kidneys absorb urobilinogen?

Answer 22

it is made into urobilin (yellow) and excreted in urine

Question 23

What happens when urobilinogen undergoes further reduction in the intestine?

Answer 23

it is made into stercobilin (red-brown) and found in poop :)

Question 24

What causes jaundice and what are the different causes?

Answer 24

Hyperbilirubinemia, elevated levels of BR in blood

1. pre-hepatic
2. intra-hepatic
3. post-hepatic

Question 25

What causes pre-hepatic jaundice?

Answer 25

increased production of unconjugated BR which causes elevated blood levels of unconjugated/indirect/free BR

Question 26

What causes intra-hepatic jaundice and some examples?

Answer 26

Impaired hepatic uptake (transporter), conjugation (transferase), or secretion of conjugated BR EX: Criggler-Najjar Syndrome (no enzyme transferase) Gilbert Syndrome

Question 27

What are some findings indicative of intra-hepatic issues?

Answer 27

High serum ALT/AST, Conjugated BR in urine

Question 28

What causes post-hepatic jaundice?

Answer 28

Cannot excrete billirubin, caused by decreased bile flow due to bile/gull stones

Question 29

What are some findings indicative of post-hepatic issues?

Answer 29

elevated blood levels of conjugated BR, BR in urine (dark), pale stool, not yellow urine

Question 30

What are neonatals deficient of and why (causes neonatal jaundice known as physiological jaundice)?

Answer 30

Deficient in UDP-GT (adds glucuronal to bilirubin) enzyme at birth-> fetal hemoglobin changes to HbA, cannot keep up with amount of bilirubin (NORMAL)

Question 31

What is a treatment for neonatal jaundice (2)?

Answer 31

Blue fluorescent light (converts BR to more soluble isomers) | Tinmesoporphyrin (strong inihibtor of heme oxygenase) stops formation of BR

Question 32

What is Crigler-Najjar Syndrome and what are the different types?

Answer 32

Syndrome resulting from deficiency of UDP-GT Type I: complete absence of gene : Severe Hyperbilirubinemia, ultimately need liver transplant Type II: Benign form, enzyme has 10% activity

Question 33

What is Gilbert Syndrome?

Answer 33

Common/Benign, Results in 25% activity of UDP-GT enzyme | Serum BR increases when fasting, stressed, or with alcohol

Question 34

What is hepatitis and what can it cause (regaurding BR as well)?

Answer 34

It is inflammation of the liver, leading to dysfunction. Caused by Hep A,B,C, alcoholism Increases levels of unconjugated and conjugated BR in blood, causing (intra-hepatic jaundice) yellow discoloration and dark urine

Question 35

BRUISING breaks down from heme to iron

Answer 35

Hg--> Heme-Red Biliverdin-Green Bilirubin-Orange Hemosiderin (iron)- reddish brown