Hemoglobin Synthesis and Catabolism

What are the two major components of hemoglobin

1. heme

2. goblin

What important atom is contained within heme

Iron

(Fe²+ → ferrous iron)

What large ring structure surrounds the iron in heme

protoporphyrin IX

What component of hemoglobin actually binds oxygen

Fe ²+ within the heme group

What globin chain makes up normal adult hemoglobin

α₂β₂

How many globin polypeptide chains are present in hemoglobin

4

How many heme groups are associated with one hemoglobin molecule

4 heme groups

(one associated with each globin chain)

What is the maximum number of O₂ molecules that one hemoglobin molecule can carry?

4 O₂ molecules

Mature RBCs lack mitochondria, how can RBCs synthesize heme if part of heme synthesis requires mitochondria

heme synthesis occurs while RBCs are still immature erythroid cells

immature RBC precursors still possess the cellular machinery necessary for heme synthesis

Can mature RBCs synthesize new heme

no

What is the primary job of the mature RBCs

carry oxygen

In what two cellular components does heme synthesis occur

mitochondria + cytoplasm

Where does heme synthesis BEGIN

mitochondria

Where does heme synthesis end

mitochondria

mitochondria → cytoplasm → mitochondria

What 2 molecules begin heme synthesis

glycine + succinyl- CoA

What product is formed from glycine + succinyl - CoA

δ - aminolaevulinic acid (ALA)

What enzyme catalyzes glycine + succinyl- CoA → ALA

AKA synthase

or

δ - aminolevulinate synthase

What is the rate limiting enzyme of heme synthesis

ALA synthase

What molecule negatively regulates ALA synthase

Heme

too much downstream heme feeds back and inhibits ALA synthase

What type of regulation occurs when heme inhibits ALA synthase

Negative feedback ibhibition

What would happen if functional ALA synthase were absent

heme synthesis could no proceed normally, impairing hemoglobin production → oxygen transport

What condition is associated with ALA synthase deficiency

sideroblastic anemia

After ALA is produced in the mitochondrion, where does it go

into the cytoplasm

How many ALA molecules combine for form porphobilinogen

2 ALA molecules

What enzyme converts ALA into porphobilinogen

ALA dehydratase

or

porphobilinogen synthase

What major toxin inhibits ALA dehydrase

lead

Why can lead poisoning produce anemia

lead inhibits enzymes involved in heme synthesis, impairing hemoglobin formation and therefore oxygen-carrying capacity

What is the product of ALA dehydratase activity

Porphobilinogen (PBG)

What enzyme acts on porphobilinogen to produce hydroxymethylbilane

porphobilinogen deaminase

or

uroporphyrinogen I synthase

Deficiency of porphobilinogen deaminase is associated with what disease

acute intermittent porphyria

What intermediate follows porphobilinogen in this pathway

hydroxymethylbilane

Hydroxymethylbilane is subsequently converted into what porphyrin intermediate

Uroporphyrinogen III

Uroporphyrinogen II is subsequently converted into what intermediate

Coproporphyrinogen III

What major porphyrin ring is produced before iron is inserted

protoporphyrin IX

What enzyme inserts iron into protoporphyrin IX

Ferrochelatase

What happens when Fe²+ is inserted into protoporphyrin IX

heme is formed

Where does iron insertion into protoporphyrin IX occur

mitochondria

What major toxin inhibits ferrochelatase

lead

What two heme synthesis enzymes does lead inhibit

1. ALA dehydratase

2. Ferrochelatase

extremely testable

Which lead-inhibited enzyme was described as producing the more serious problem: ALA dehydratase of ferrochelatase

ferrochelatase inhibition

Why was ferrochelatase inhibition described as more serious

By this point in the pathway, the large porphyrin ring has already been produced

failure to complete the pathway allows porphyrin structures to accumulate/ precipitate and produce more tissue effects

Draw the simplified heme synthesis pathway

Glycine + succinyl-CoA

↓ ALA synthase

ALA

↓ ALA dehydratase

Porphobilinogen

↓

Hydroxymethylbilane

↓

Uroporphyrinogen III

↓

Coproporphyrinogen III

↓

Protoporphyrin IX

↓ Ferrochelatase + Fe²+

HEME

What is porphyrias

rare inherited or sometimes acquired disorders of heme synthesis resulting from defects in enzymes of the pathway

Why are many porphyrias inherited

a mutation in a gene can cause deficiency of an enzyme required for heme synthesis

Why can some porphyrias be acquired

Environmental/toxic exposures can inhibit heme-synthesis enzymes

ex: lead

What accumulates in porphyrias

porphyrins or porphyrin precursors; the specific pattern depends on which enzyme is deficient

Why do different enzyme deficiencies produce different porphyrias

Blocking the pathway at different locations causes:

Different intermediates to accumulate

What common skin-related finding can occur with porphyrias

photosensitivity

What can happen when photosensitive porphyrins are exposed to light

oxidative/free-radical injury can occur, damaging

• cellular membranes

• tissues

• lysosomal structures

and contributing to skin burning/itching

What enzyme deficiency causes acute intermittent porphyria (AIP)

porphobilinogen deaminase deficiency

or

uroporphyrinogen I synthase

What drug class was associated with triggering acute intermittent porphyria

barbiturates

antiepileptic medications were also mentioned as potential drug clues

What urinary clue was emphasized for acute intermittent porphyria

dark urine

What GI symptoms are associated with AIP

• nausea

• vomiting

• diarrhea/ GI disturbances

Patient develops GI/ neurovisceral symptoms and dark urine after taking barbiturates. What should you think?

Acute intermittent porphyria

What porphyria was described as the most common porphyria

porphyria cutanea tarda (PCT)

What enzyme deficiency is associated with porphyria cutanea tarda

Uroporphyrinogen decarboxylase

What major skin finding is associated with PCT

Photosensitive blistering, especially on sun-exposed skin

What substance is strongly associated with precipitating PCT

Alcohol

What infections are associated with PCT

Hepatitis B or C

What age range is associated with PCT

Approximately the 4th - 5th decades of life

50 year old heavy drinker who works outdoors develops painful blisters on the backs of his hands. Diagnosis?

Porphyria cutanea tarda

“Alcoholic playing golf” → PCT

What enzyme deficiency was associated with variegate porphyria

protoporphyrinogen oxidase deficiency

What clinical manifestations were associated with variegate porphyria

• skin damage

• GI disturbances

• muscle weakness

• seizures

• anxiety

• hallucinations

What age group was associated with erythropoietic porphyria

early childhood

What characteristic clue can occur in a child with erythropoietic porphyria

immediate pain/crying with bright sunlight exposure

What two heme-synthesis enzymes should you immediately associate with lead poisoning

ALA dehydratase

ferrochelatase

What toxicity besides impaired heme synthesis is associated with lead

neurotoxicity

What pediatric environment clue should make you think lead poisoning

child living in an older home with exposure to old paint

What occupational clue was mentioned for lead exposure

work involving old houses/plumbing

Where does functional globin synthesis occur

cytoplasm (of immature erythroid cells such as normoblasts/reticulocytes)

On which chromosome are the alpha-globin genes located

chromosome 16

specifically told to memorize this!!!!!!!

On which chromosome is the beta-globin gene cluster located

Chromosome 11

alpha =

beta =

alpha = 16

beta = 11

What disorder results from imbalance in production of alpha versus non-alpha globin chains

thalassemia

what is the basic concept behind thalassemia

imbalanced globin-chain synthesis

(one globin chain is reduced or absent relative to the other)

What globin chains make up fetal hemoglobin

α₂γ₂

What globin chains make up the major adult hemoglobin

α₂β₂

What major globin switch occurs after birth

γ → β

the infant transitions from predominantly:

α₂γ₂ → α₂β₂

Why was postnatal hemoglobin transition connected to neonatal jaundice

the lecture describes substantial RBC turnover around birth during the transition from fetal to adult hemoglobin, increasing the amount of hemoglobin that must be degraded and therefore the bilirubin burden

What molecules make up the functional iron pool

hemoglobin

myoglobin

iron-containing enzymes

What molecules constitute major iron storage pools

ferritin + hemosiderin

What is the major iron transport protein

transferrin

TRANSferrin = TRANSports iron

What is the major concept behind ferritin

Iron storage/ buffering

What was another name for for the ferritin system

iron buffer system

Where is dietary iron primarily absorbed

duodenum

In what oxidation state is iron preferentially absorbed

Fe2+ - ferrous iron

What transporter brings Fe2+ into enterocytes

DMT1

Which two proteins were especially important for iron regulation

hepcidin

ferroportin

What does hepcidin do to ferroportin

promotes ferroportin internalization/ degredation

What is the overall effect of increased hepcidin

decreased circulating iron avaliability

What is the overall effect of decreased hepcidin activity

increased iron availability/ absorption (potentially contributing to iron overload)

What disease is characterized by pathologic iron overload and was specifically mentioned

Hemochromatosis

Approximately how long does a normal RBC circulate before becoming senescent

approximately 120 days

what cells remove senescent RBCs from circulation

macrophages (of the reticuloendothelial system)

What happens to globin during hemoglobin breakdown

it is degraded into amino acids, which can be recycled

What happens to iron during hemoglobin breakdown

it is recycled/ stored for reuse

What happens to the porphyrin portion of heme during catabolism

it ultimately contributes to bilirubin formation for elimination

what enzyme initiates heme breakdown

heme oxygenase

what bilirubin form is initially produced during hemoglobin catabolism before hepatic conjugation

unconjugated bilirubin

where is bilirubin conjugated

liver