Heme Synthesis & Breakdown Flashcards by SD Colin Hemond

Structure of Hemoglobin (Hb)

Four globular protein sub-units each bound to an iron containing heme.

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Describe porphyrin riing structure of heme.

Four 5 membered rings contain nitrogen connected by single carbon bridges.

Iron present in the center in ferrous state.

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What is heme present in?

Hb, myoglobin, and cytochromes

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Oxidation to ferric state causes what in Hb?

Inactivates it, forms methemoglobin.

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Where does biosynthesis of heme occur?

Liver and erythroid cells

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Feedback inhibition caused by Heme

delta-ALA synthase

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What does lead poisoning inactivate in heme synthesis?

What does this result in.

ALA dehydratase (contains Zn) and ferrochelatase (contains Fe).

Lower energy as cytochromes are not synthesized

Lower heme production

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What does Lead Poisoning cause an accumulation of?

What diseases do these result in?

ALA and Protoporphyrin IX

ALA is neurotoxic and resembles neurotransmitter GABA

Neurological disease and Anemea

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What are inherited metabolic disorders that casue defects in heme synthesis?

Porphyria

Acute hepatic - neurological symptoms

Erthropoietic- skin, photosensitivity

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Porphyria caused by defective PBG deaminase in liver.

What is the name, type, and symptoms?

Acute intermittent porphyria

Hepatic

Neurological dysfunction

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Porphyria caused by defective Uroporphyrinogen III synthase (in erythrocytes)

What is the name, type, and symptoms?

Congenital erythropoietic porphyria

Erythroporphyric

Photo sensitivity, red color in urine and teeth

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Porphyria caused by defective Uroporphyrinogen decarboxylase.

What is the name, type?

Porphyria cutanea tarda (PCT)

Hepatoerythropoietic

Photosynsitive, wine red urine, bullae on skin of exposed area to sun

MOST COMMON

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Porphyria caused by defective Protoporphyrinogen IX oxidase.

What is the name, type, and symptoms?

Variegate porphyria

Hepatic

Famous People - photosentivity and neurological delay development

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Congenital erythropoietic porphyria results in the build up of what? What symtops are produced?

Results in build up of uroporphyrinogen I and its oxidation product uroporphyrin I

Produce a red color in urine, red fluorescence in teeth, destruction of rbc, and skin photosensitivity

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How does heme degreadation take place?

Reticulo-endothelial system

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What are the normal levels of bilirubin in the body?

Unconjugated/indirect/free (0.2-0.9 mg/dl)

Conjugated/direct (0.1-0.3 mg/dl)

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What is pre-hepatic jaundice caused by?

Increased production of unconjugated BR

Excess hemolysis (hemolytic anemias)

Internal hemorrhage

Capacity of liver to uptake and/or conjugate and/or
excrete BR exceeded

E.g., glucose-6-PO4 dehydrogenase deficiency

Problems with incompatibility of maternal-fetal blood
groups (in neonates)

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Impaired hepatic uptake, conjugation, or secretion of conjugated BR.

Caused by genralized hepatic dysfunction

Intra-hepatic jaundice

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Intrahepatic Jaundice findings

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Variable increases in unconjugated and conjugated BR depending on the cause (pre- or post-conjugation)

Increase in serum ALT and AST

Conjugated BR detected in urine

Disease examples of Intrahepatic dysfunction

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Criggler-Najjar syndrome - defect in Biliruben UDP gluconyltransferase

Gilbert syndrome

Liver cirrhosis

Viral hepatitis

Problems with BR excretion lead to this type of Jaundice.

What are the various names for it?

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Post-hepatic Jaundice

AKA Cholestatic jaundice or cholestasis

What can cause Post Hepatic Jaundice

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Obstruction to biliary drainage (in liver or bile duct)

Cholangiocarcinoma

Gall stones

Infiltrative liver disease

Lesions (tumor, abscess or granulomatous disease)

Drugs (anabolic hormones, chlorpromazine,
phenytoin)

What are the findings in post-hepatic jaundice

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Elevated blood levels of conjugated BR

Conjugated BR is present in urine (dark)

Small increases in unconjugated form

Elevated alkaline phosphatase (ALP)

No urobilinogen in urine

No stercobilin in feces (pale stool)

Neonatal jaundice (physiological jaundice) is caused by a deficiency in what enzyme?

Explain how bilirubin accumulates.

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Immature hepatic metabolic pathways

UDP-GT enzyme

The breakdown of fetal hemoglobin to adult hemoglubin causes accumpulation of billirubin

How is physiological jaundice treated?

When exposed to **blue flourescent light**, bilirubin undergoes photoconversion to form more soluble isomers. Or inject strong **inhibitor of heme oxygenase**)

Physiological Jaundice is worrisome why?

**Severe hyperbilirubinemia** If it diffuses to basal ganglia it can cause encephalopathy **(kernicturus)**

What are the 5 therapies for UDP-GT-related disorders?

Blood transfusions Phototherapy Heme oxygenase inhibitors Oral calcium phosphate and carbonate (form complexes with bilirubin in gut) **Liver transplantation** (before brain damage occurs and before phototherapy becomes ineffective)

What is Hepatitis and what are it's causes?

Inflammation of the liver which may lead to liver dysfunction Causes – viral infections (Hep A, B, C), alcoholic cirrhosis, liver cancer.

Symptoms of Hepatitis

Increased levels of unconjugated and conjugated BR in blood BR accumulates in skin and sclera of the eyes, causing yellow discoloration Dark, tea colored urine

What are the two isoforms of **ALAS** and where are they found? How are they regulate?

**ALAS I (ubiquitous)** **ALAS II (only in erythroid cell of bone marrow)** Both regulated by **heme and hemin** ALASII has an **iron response element** which increases it's transcriiption in the presence of Iron.

What reaction does **ALA synthase catalyze**? Where does this occur? What is the required vitamin?

**Gly + Succinyl CoA** to **Aminovulinic Acid (ALA)** ## Footnote **Mitochondria** **B6 - Needs PLP**

What reaction is catalzed by **ALA dehydratase?** Where is this done?

**2** **ALA** to **1 Porphobilinogen (PBG)** ## Footnote **Cytosol**

What reaction does **porphobilinogen deaminase** catalyze? What porphyria can is cause

**4 PBG** to **1 Hydroxymethylibilane** ## Footnote **Acute intermittent porphyria**

Enzyme that catalyzes **Protophyrin to Heme?**

**Ferrochelatase**

What reaction does **Uroporphyrinogen III** **co****synthase** catalyze? What is the porphyria?

**Hydroxymethylbilane to Uroporphrinogen III** **Congenital erythropoietic porphyria**

Enzyme catalyzes the reaction of **uroporphyrinogen III to coproporphyrinogen III.** What porphyria?

**Uroporphyrinogen decarboxylase** ## Footnote **Porphyria cutanea tarda**

What reaction is catalyzed by **Uroporphyrinogen decarboxylase?** What is the porphyria?

**Uroporphyrinogen III to Coporphyrinogen III** **Porphyria Cuteana tarda**

What catalyzes the reaction of **protophyrinogen IX to protophyrinogen**? What is the porphyria?

**Protophyrinogen oxidase** **Variegate porphyria**

What does **heme oxidase** produce?

**Bilividerin IXa and Fe3+** from Heme CO2 as well

What reaction does **Biliverdin reductase** catalyze? What does it use?

**Billiverdin to billirubin** Uses NADPH to make NADP+

What enzyme facilatates the activation of glucose for conjugation of **Billiruben**? How does it do so?

**UDP glucose dehydrogenase** **UDP Glucose** + 2NAD⁺ = **UDP-glucuronate** + 2NADH + 2H⁺ \

What is the rate limiting step in bilirubin removal from blood?

**Biliruben UDP gluconyltransferase** **2 UDP-glucouronate + Bilirubin = Bilirubin digluronide**

Microcrobes convert **Bilirubin-diglucuronide** into what? What does the kidney do after? What about the intestine?

**Bilirubin** and then **Urobilinogen** Kidney converts to **Urobillin** (yellow) Intestine converts to **Stercobilin** (brown) BUUS

Results from deficiency of UDP-GT, complete absence of the gene

**Crigler-Najjar Syndrome Type 1**

Benign form of desease. Results from a **mutation in the UDP-GT gene.** Enzyme has less activity (10% activity)

**Crigler-Najjar Syndrome Type II**

Relatively common diease (2-10% of population), results in 25% of regular UDP-GT activity. Serum BR \<6mg/dl but may increase with fasting, stress, or alcohol.

**Gilbert Syndrome**

Heme Synthesis & Breakdown Flashcards

(46 cards)