MBBCh BMS 202: Hemoglobin Structure

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Questions and Answers

What is the primary function of mature red blood cells (RBCs)?

To transport nutrients

To contain hemoglobin (correct)

To synthesize heme

To produce hormones

Which of the following statements accurately describes the structure of adult hemoglobin?

It consists of two heme groups and three globin chains.

It is a tetramer made up of four heme groups and four globin chains. (correct)

It is a monomer formed of a single polypeptide chain.

It comprises one heme group and one globin chain.

Where does the biosynthesis of heme primarily take place?

In the liver

In the lungs

In the spleen

In the bone marrow (correct)

Which type of hemoglobin is the most prevalent in adults?

Adult hemoglobin type A (HbA) Signup and view all the answers

What characterizes porphyrias?

They are disorders resulting from enzymatic defects in heme synthesis. Signup and view all the answers

Which of the following correctly identifies a component of the heme structure?

Four pyrrole rings linked by methenyl bridges Signup and view all the answers

What is the approximate lifespan of red blood cells in peripheral circulation?

120 days Signup and view all the answers

Which globin chain lengths are characteristic of adult hemoglobin?

α chain: 141 amino acids; β chain: 146 amino acids Signup and view all the answers

What is the primary regulatory step in heme synthesis?

Inhibition of ALA synthase by heme Signup and view all the answers

Which factor stimulates the activity of ALA synthase?

Erythropoietin Signup and view all the answers

Which of the following is NOT a manifestation of porphyria?

Increased appetite Signup and view all the answers

What is a key characteristic of the acute intermittent porphyria?

Neuropsychiatric symptoms Signup and view all the answers

What laboratory finding is commonly seen during an acute attack of porphyria?

Increased PBG in urine Signup and view all the answers

Which condition is classified as an acquired porphyria?

Lead poisoning Signup and view all the answers

How does heme influence ALA synthase activity?

It inhibits its activity Signup and view all the answers

What is one of the main causes of porphyria?

Deficiency of heme synthesis enzymes Signup and view all the answers

Which organ is not a major site for the biosynthesis of heme?

Heart Signup and view all the answers

Which enzyme catalyzes the committed step in heme synthesis?

delta-aminolevulinic acid synthase 1 Signup and view all the answers

What is the primary consequence of lead poisoning regarding enzyme activity in heme synthesis?

Inhibition of ALA dehydratase Signup and view all the answers

Which of the following substances would inhibit the activity of ALA synthase-1?

Hemin Signup and view all the answers

From which substrates is ALA synthesized?

Glycine and succinyl CoA Signup and view all the answers

Which enzyme is NOT involved in heme synthesis?

Citrate synthase Signup and view all the answers

What is the role of ALA synthase-2 in heme synthesis?

Regulates heme synthesis in erythroid tissues Signup and view all the answers

Which of the following is true regarding porphyrias?

They are caused by defects in heme synthesis. Signup and view all the answers

Which organ is primarily responsible for the synthesis of hemoglobin?

Bone marrow Signup and view all the answers

What is the first step of heme synthesis?

Synthesis of ALA Signup and view all the answers

Which enzyme is inhibited by lead poisoning, leading to the accumulation of Protoporphyrin IX in blood?

Ferrochelatase Signup and view all the answers

Where in the cell does the synthesis of Porphobilinogen (PBG) occur?

In the cytosol Signup and view all the answers

What are the starting materials for the synthesis of Delta (5) Aminolevulinic acid (ALA)?

Succinyl CoA and Glycine Signup and view all the answers

Which enzyme is described as the key regulatory step in heme synthesis?

ALA Synthase Signup and view all the answers

What is the last step of heme synthesis?

Generation of heme Signup and view all the answers

Where does synthesis of the last three reactions of heme synthesis occur?

In the mitochondria Signup and view all the answers

Study Notes

Learning Outcomes

Understand the structure of heme.
Identify the primary locations of heme biosynthesis.
Describe the heme synthetic pathway and its regulation.
Recognize porphyrias as enzymatic defects affecting heme synthesis.

Red Blood Cells (RBCs)

Shape: Biconcave discs, enhancing surface area for gas exchange.
Diameter: Approximately 7 microns.
Life span: 120 days in peripheral circulation.
Synthesized in the bone marrow.
Mature RBCs lack a nucleus and mitochondria and mainly function to transport oxygen (O2) and carbon dioxide (CO2) via hemoglobin.

Hemoglobin

A respiratory pigment made of heme and globin, synthesized in immature RBCs.
Normal hemoglobin concentration:
- Adult males: 13.5 – 16.5 gm/dl.
- Adult females: 12.0 – 14.8 gm/dl.
Types of hemoglobin:
- Normal: HbA (97%), HbA2 (2%), HbF (1%), HbA1c (glycosylated).
- Abnormal: Carboxyhemoglobin, Methemoglobin, Sulfhemoglobin.

Structure of Hemoglobin

Composed of 4 heme groups and 4 globin chains (2 alpha and 2 beta).
Alpha chain: 141 amino acids; Beta chain: 146 amino acids.

Structure of Heme

Heme is an iron porphyrin, a cyclic compound formed by four linked pyrrole rings.
Iron complexes with nitrogen atoms in the porphyrin structure.

Importance of Heme

Essential component of various hemoproteins:
- Hemoglobin
- Myoglobin
- Cytochromes (C & P450)
- Catalase
- Peroxidase

Sites of Heme Synthesis

Predominantly occurs in:
- Bone marrow for hemoglobin synthesis.
- Liver for cytochrome P450 synthesis.
Cellular locations:
- Mitochondria (first and last reactions).
- Cytosol (intermediate steps).

Pathway of Heme Synthesis

Synthesis begins in mitochondria with the production of delta-aminolevulinic acid (ALA).
Transition to cytosol includes steps like the synthesis of porphobilinogen, uroporphyrinogen III, and coproporphyrinogen III.
Final reactions return to mitochondria for the production of heme.

Key Steps in Heme Synthesis

First step: Synthesis of ALA from succinyl CoA and glycine, catalyzed by ALA synthase (key regulatory step).
Last step: Formation of heme by combining iron with protoporphyrin IX, catalyzed by ferrochelatase.

Lead Poisoning and Heme Synthesis

Lead poisoning inhibits ALA dehydratase and ferrochelatase, leading to the accumulation of porphyrins and ALA in blood and urine.

Regulation of Heme Synthesis

The regulatory step is controlled by heme and other factors such as glucose and steroids.
ALA synthase activity is inhibited by hemin and stimulated by iron availability, hypoxia, and erythropoietin.

Disorders of Heme Synthesis (Porphyrias)

Characterized by increased blood porphyrins and urinary excretion.
Caused by enzyme deficiencies in the heme synthesis pathway.
Manifestations include dark urine, photosensitivity, skin rash, neuropathy, hypertension, and abdominal pain.
Classification:
- Inherited and acquired (e.g., lead poisoning, alcoholic liver disease).

Diagnosis of Porphyrias

Measurements of porphobilinogen (PBG) in urine and heme synthesis intermediates in various biological samples.

Case Discussion on Lead Poisoning

Symptoms include abdominal pain, mental status changes, and fatigue.
Lead interferes primarily with ALA dehydratase enzyme.

Take Home Messages

Heme biosynthesis predominantly occurs in bone marrow and liver.
Glycine and succinyl CoA are starting materials for porphyrin synthesis.
ALA synthesis, catalyzed by ALA synthase, is the committed step.
Porphyrias result from defects in the heme synthesis pathway, leading to porphyrin accumulation.

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Description

Explore the intricate details of hemoglobin structure and the synthesis of heme in this MBBCh BMS 202 module. Understand key concepts and outcomes associated with the locomotor system and integument module. Prepare to deepen your knowledge in medical biochemistry under the guidance of Dr. Ghada Helal.