Lect 11 Heme Synthesis & Breakdown Flashcards Preview

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Flashcards in Lect 11 Heme Synthesis & Breakdown Deck (22)
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1
Q

Hemoglobin and Heme

What are the features of Porphyrin Rings (Heme)?

What happens with oxidation of iron?

Where is Heme located?

A

Four 5-membered rings (Pyrroles) with Iron in the center (Ferrous)

Oxidation to Ferric state inactivates Hb

Hb, Myoglobin, Cytochromes

2
Q

Biosynthesis of Heme

Where does it primarily occur?

What is caused by defects in any stage?

A

Liver & BM (Erythroid Cells)

Porphyrias

3
Q

Heme Biosynthesis Phase I: Mitochondria

What is this process? (1 Step)

What enzyme is used?

What cofactor is needed?

A

Glycine + Succinyl CoA –> ALA

ALA synthase

Vitamin B6 (PLP)

4
Q

Heme Biosynthesis Phase II: Cytosol

What is this process? (4 Steps)

A

2 ALA –> Porphobillinogen (PBG) via ALA Dehydratase

PBG –> Hydroxymethylbilane via PBG Deaminase *

Hydroxymethylbilane –> Uroporphyrinogen III via Uroporphyrinogen III Synthase *

Uroporphyrinogen III –> Coproporphyrinogen III via Uroporphyrinogen Decarboxylase *

5
Q

Heme Biosynthesis Phase III: Mitochondria

What is the process? (3 Steps)

A

Coproporphyrinogen III –> Protoporphyrinogen IX via Coproporphyrinogen Oxidase *

Protoporphyrinogen IX –> Protoporphyrin IX via Protoporphyrinogen IX Oxidase *

Protoporphyrin IX + Fe2+ –> Heme via Ferrochelatase *

6
Q

Lead Poisoning

What does lead inactivate in the Heme biosynthesis pathway?

What accumulates?

What does this cause?

What else is impacted?

A

ALA Dehydratase and Ferrochelatase

ALA and Protoporphyrin IX

Anemia

Energy production due to decreased cytochome synthesis

7
Q

Porphyrias

What are they caused by?

What are the different types and associated sx?

A

Defects in heme synthesis

Acute Hepatic (Liver) –> Neurological Sx

Erythropoietic (BM) –> Skin, Photosensitivity

8
Q

Acute Intermittent Porphyria

What is the defective enzyme?

What type of porphyria?

A

PBG Deaminase

Hepatic

9
Q

Congenital Erythropoietic Porphyria

What enzyme is defective?

What type of Porphyria?

What builds up?

What are the Sx?

A

Uroporphyrinogen III Synthase

Erythropoietic

Uroporphyrinogen I & oxidation product Uroporhyrin I

Red colored urine, Red fluorescence in teeth, Skin photosensitivy

10
Q

Porphyria Cutanea Tarda (Most Common in US)

What enzyme is defective?

What type of Porphyria?

A

Uroporphyrinogen Decarboxylase

Hepatoerythropoietic

11
Q

Variegate Porphyria

What enzyme is defective?

What type of Porphyria?

A

Protoporphyrinogen IX Oxidase

Hepatic

12
Q

Heme Degradation

What does Heme oxygenase do and what does it require?

What gets released afterwards?

What happens to Ferrous iron in Heme?

What is the product after Heme and what does it require to be converted into Bilirubin?

A

Removes connection between pyrrole rings of heme by adding oxygen

Carbon Monoxide (CO)

Oxidized to Ferric iron

Biliverdin requires Biliverdin reductase to form Bilirubin

13
Q

Conjugation of Bilirubin (BR)

What type of BR is insoluble and bound ot Albumin and where is it taken to?

What happens to BR to make it soluble?

What is conjugation of bilirubin?

Where is it sent afterwards?

A

Free/Unconjugated/Indirect BR transported to the liver for Hepatic uptake

Conjugated with Glucuronic acid

UDP-Glucuronate and Bilirubin combine using BR UDP glucuronyltransferase to form BR-Diglucuronide (Rate Limiting Step of BR removal)

Releasing into Gall Bladder as Bile

14
Q

BR in Response to Food

What is BR-Diglucuronide reduced to in the intestines?

Where can that product travel to next?

A

Urobilinogen

Some reabsorbed by kidneys to produce urobilin (urine)

Some receives further reduction to stercobilin (feces)

15
Q

Jaundice

Also known as?

What causes this?

What are normal ranges of unconjugated and conjugated BR?

A

Hyperbilirubinemia

Elevated levels of BR in the blood

Unconjugated: 0.2 -0.9

Conjugated: 0.1 -0.3

16
Q

Pre-Hepatic Jaundice

What is the cause?

Why would this occur?

A

Increased production of unconjugated/indirect BR

Excess Hemolysis, Internal Hemorrhage; G6P Dehydrogenase Deficiency (No NADPH)

17
Q

Intra Hepatic Jaundice

What is the cause?

Associated diseases?

A

Impaired hepatic uptake, conjugation, or secretion of conjugated BR

Criggler-Najjar Syndrome & Gilbert Syndrome

18
Q

Post Hepatic Jaundice

Caused by what?

Findings?

A

Problems with BR excretion

Elevated conjugated BR in blood

Conjugated BR in urine (dark) and no urobilinogen

No urobilinogen in feces (pale stool)

19
Q

Neonatal Jaundice

Newborns can develop jaundice due to elevated unconjugated BR, what is this called?

What is deficient?

What is being broken down in newborns?

What is the treatment?

A

Physiological Jaundice

UDP-GT enzyme

Fetal Hb as it is replaced with Adult Hb

Phototherapy

20
Q

UDP-GT Related Disorders

Crigler-Najjar Syndrome Type I cause and what it leads to?

What can accumulate?

Therapy?

A

Complete absence of the gene leading to severe hyperbilirubinemia

BR accumulates in brain of babies –> encephalopathy (kernicturus) and brain damage

Blood transfusions; Phototherapy; Heme oxygenase inhibitors; Oral CaPO4 and CO3; Liver Transplant

21
Q

UDP-GT Related Disorders

Criggler Najjar Syndrome Type II cause?

Gilbert Syndrome cause?

A

Mutation in UDP-GT gene causing 10% enzyme activity

Reduced activity of UDP-GT (25% activity)

22
Q

Hepatitis

Causes?

What are the findings?

Where does BR accumulate causing yellow discoloration?

A

Viral infections (Hep A, B, C); Alocholic Cirrhosis; Liver Cancer

Increased levels of unconjugated and conjugated BR in blood

Skin and Sclera of the eyes