T4 - Globulin Synthesis

How many polypeptide subunits make up an adult hemoglobin (HbA) molecule?

Four (two alpha, two beta)

What is the oxidation state of iron in functional heme?

Ferrous (Fe2+)

What is the coordination number of the ferrous ion in a heme molecule?

Six

Which amino acid residue on the globin protein forms a coordinate bond with the heme iron?

Proximal histidine

In which two cellular compartments does heme synthesis occur?

Mitochondria and cytoplasm

Which two molecules condense to form delta-aminolevulinic acid (ALA)?

Glycine and succinyl-CoA

Which enzyme catalyzes the rate-limiting step of heme synthesis?

ALA synthase (ALAS)

What essential cofactor is required by ALA synthase?

Vitamin B6 (pyridoxal phosphate)

Which enzyme catalyzes the final step of heme synthesis by inserting Fe2+?

Ferrochelatase

Which two enzymes in the heme synthesis pathway are directly inhibited by lead?

ALA dehydratase and ferrochelatase

What is the primary site of heme production for cytochrome enzymes?

Liver

Does heme synthesis occur in circulating reticulocytes?

No

How does the end-product heme regulate its own synthesis in the liver?

Feedback inhibition of ALA synthase 1

How does iron availability regulate heme synthesis in erythroid cells?

Increases ALAS2 stability

What class of drugs induces hepatic CYP450 and can precipitate acute porphyria attacks?

Barbiturates

Which condition results from a deficiency in porphobilinogen deaminase?

Acute intermittent porphyria (AIP)

What are the two primary accumulating intermediates in Acute Intermittent Porphyria?

Aminolevulinic acid (ALA) and porphobilinogen (PBG)

Are photosensitivity and blistering seen in Acute Intermittent Porphyria?

No

What is the most common porphyria?

Porphyria cutanea tarda (PCT)

Which enzyme is deficient in Porphyria Cutanea Tarda (PCT)?

Uroporphyrinogen decarboxylase

Does Porphyria Cutanea Tarda (PCT) present with photosensitivity?

Yes

What characteristic urine color change occurs during an acute attack of AIP or PCT?

Dark red or brown

What intravenous carbohydrate is given to suppress ALA synthase 1 during an acute porphyria attack?

Dextrose (Glucose)

What exogenous blood product is administered to downregulate ALAS1 in severe porphyria attacks?

Hematin (Hemin)

What specific RBC inclusion is a hallmark of lead poisoning on a peripheral smear?

Basophilic stippling

Why does lead poisoning cause basophilic stippling in red blood cells?

Inhibition of rRNA degradation

What specific bone radiographic finding is classically seen in childhood lead poisoning?

Dense metaphyseal lines (Lead lines)

Which chelating agent is administered orally for moderate lead poisoning?

Dimercaptosuccinic acid (DMSA)

Which intravenous chelating agent is used for severe lead poisoning with encephalopathy?

Calcium disodium EDTA

What X-linked genetic mutation causes hereditary sideroblastic anemia?

ALAS2 gene mutation

What characteristic bone marrow finding is seen in sideroblastic anemia?

Ringed sideroblasts

What is the underlying pathophysiology of ringed sideroblasts?

Iron accumulation in mitochondria

Which antibiotic classically causes acquired sideroblastic anemia by depleting vitamin B6?

Isoniazid

What are the component globin chains of fetal hemoglobin (HbF)?

Two alpha and two gamma chains (a2y2)

What are the component globin chains of embryonic Hemoglobin Gower 1?

Two zeta and two epsilon chains (z2e2)

Which human chromosome houses the alpha-globin gene cluster?

Chromosome 16

Which human chromosome houses the beta-globin gene cluster?

Chromosome 11

Why does HbF have a higher affinity for oxygen than HbA?

Binds 2,3-DPG less strongly

Around what postnatal age does the gamma-to-beta globin switch predominantly occur?

Birth to 6 months

What happens to the oxygen-hemoglobin dissociation curve when blood pH decreases?

Shifts to the right (Bohr effect)

How does increased 2,3-DPG affect hemoglobin's oxygen affinity?

Decreases affinity (shifts curve right)

Which phenomenon describes oxygen unloading in tissues due to increased H+ and CO2?

Bohr effect

Which phenomenon describes CO2 unloading in the lungs due to high oxygen tension?

Haldane effect

What inactive hemoglobin derivative contains oxidized ferric (Fe3+) iron?

Methemoglobin

What hemoglobin derivative is formed by the binding of carbon monoxide?

Carboxyhemoglobin

What hemoglobin derivative serves as a long-term marker of glycemic control?

Glycohemoglobin (HbA1c)

In which cellular system are senescent red blood cells primarily destroyed?

Reticuloendothelial macrophages

What enzyme converts heme to biliverdin during RBC breakdown?

Heme oxygenase

What enzyme reduces biliverdin to unconjugated bilirubin?

Biliverdin reductase

How is unconjugated bilirubin transported in the blood?

Bound to albumin

Which liver enzyme conjugates bilirubin to make it water-soluble?

UDP-glucuronosyltransferase (UGT1A1)

What are the two major intestinal derivatives of conjugated bilirubin?

Stercobilinogen and urobilinogen

Which compound gives feces its characteristic brown color?

Stercobilin

Which compound gives urine its characteristic yellow color?

Urobilin

What is the primary absorption site for dietary iron?

Duodenum and proximal jejunum

Which enterocyte apical transporter mediates the uptake of non-heme ferrous iron?

Divalent metal transporter 1 (DMT1)

Which enterocyte basolateral protein exports iron into the portal circulation?

Ferroportin

Which liver-derived peptide hormone regulates iron homeostasis by degrading ferroportin?

Hepcidin

Which plasma protein transports ferric iron (Fe3+) to tissues?

Transferrin

Which intracellular protein stores iron to prevent free radical toxicity?

Ferritin

What type of genetic defect primarily causes thalassemia?

Quantitative defect in globin chain synthesis

What type of genetic defect primarily causes hemoglobinopathies like Sickle Cell Disease?

Qualitative defect in globin chain structure

What is the specific amino acid substitution in Hemoglobin S (HbS)?

Glutamic acid to valine at position 6

What is the specific amino acid substitution in Hemoglobin C (HbC)?

Glutamic acid to lysine at position 6

What is the specific amino acid substitution in Hemoglobin E (HbE)?

Glutamic acid to lysine at position 26

Which genetic mutation causes Hb Constant Spring?

Point mutation in the alpha chain stop codon

What happens to unpaired alpha-globin chains in beta-thalassemia?

Precipitate in RBC precursors causing apoptosis

What term describes the premature death of RBC precursors in the bone marrow?

Ineffective erythropoiesis

What compensatory bone change occurs due to severe ineffective erythropoiesis in thalassemia?

Bone marrow expansion (facial changes)

Most alpha-thalassemias are caused by what type of genetic mutation?

Gene deletions

Most beta-thalassemias are caused by what type of genetic mutation?

Point mutations

What condition is caused by a complete deficiency of all four alpha-globin genes?

Hydrops fetalis

Which hemoglobin tetramer predominates in hydrops fetalis (alpha-thalassemia major)?

Hemoglobin Barts (gamma 4)

What condition is caused by the deletion of three alpha-globin genes?

Hemoglobin H disease

Which hemoglobin tetramer characterizes Hemoglobin H disease?

Tetramer of beta chains (beta 4)

How does transferrin receptor 1 (TfR1) expression change as proerythroblasts mature?

Upregulated to increase iron uptake

Which specific molecule triggers the transcription and translation of globin genes?

Heme

Which red blood cell parameter determines oxygen affinity in the Tense (T) state?

Low oxygen affinity

Does hemoglobin's relaxed (R) state have a high or low affinity for oxygen?

High oxygen affinity

Which apical enterocyte enzyme reduces dietary ferric iron to ferrous iron for absorption?

Duodenal cytochrome b (Dcytb)

What basolateral enterocyte enzyme oxidizes ferrous iron to ferric iron for transferrin binding?

Hephaestin

What is the typical daily dietary iron absorption rate in a healthy individual?

1-2 mg/day

What is the normal lifespan of a mature red blood cell?

Approximately 120 days

Which cell type provides the central nursing role in a bone marrow erythroblastic island?

Macrophage

Do mature red blood cells contain the enzymes necessary for heme synthesis?

No

What specific shape do RBCs assume in Hemoglobin S disease under hypoxic conditions?

Sickled shape (Drepanocyte)

Are target cells more characteristic of thalassemia or autoimmune hemolytic anemia?

Thalassemia

Which porphyria is caused by a deficiency in coproporphyrinogen oxidase?

Hereditary coproporphyria (HCP)

Which enzyme is deficient in Variegate Porphyria (VP)?

Protoporphyrinogen oxidase

Which enzyme is deficient in Erythropoietic Protoporphyria (EPP)?

Ferrochelatase

Do conditions that increase erythropoiesis upregulate or downregulate hepcidin secretion?

Downregulate hepcidin

How does hypoxia affect hepatic hepcidin secretion?

Decreases secretion

How does systemic inflammation affect hepatic hepcidin secretion?

Increases secretion

What is the primary consequence of hepcidin upregulation during infection?

Decreased iron absorption and release

What hemoglobin derivative forms spontaneously via a non-enzymatic reaction with glucose?

Glycohemoglobin (HbA1c)

Which molecule has a 200x higher binding affinity for heme iron than oxygen?

Carbon monoxide

Does carboxyhemoglobin formation shift the oxygen dissociation curve left or right?

Left

Does hypothermia cause a left or right shift in the oxygen-hemoglobin dissociation curve?

Left shift

Which dietary factor significantly enhances the intestinal absorption of non-heme iron?

Vitamin C (Ascorbic acid)

What component of the RBC membrane provides the central structural backbone for hemoglobin?

Porphyrin ring