Hemoglobin Flashcards by Rhea Rubin

Cells less than 1mm can diffuse oxygen across their membrane. Multicellular organisms are too big for diffusion. How have they adapted?

Oxygen carriers (Hb) and circulatory systems

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Approximately how much hemoglobin is present in blood?

145 g/L = 10 mM Hb monomers

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Why do we need oxygen?

Oxidative phosphorylation; oxygen is the final electron acceptor

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Where is myoglobin found? What does it look like?

Muscle cells; a single chain of alpha helices with a heme group

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What is the function of myoglobin?

Intracellular transport and storage of oxygen

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What does hemoglobin look like? How many hemes are present? How much oxygen binds when the hemoglobin is saturated?

4 subunits (tetrameric); each of these subunits has a heme and each heme binds a molecule of oxygen
1 hemoglobin molecule= 4 heme= 4 oxygen

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What does apo mean in terms of hemoglobin?

Has the two alphas and two betas, but no heme

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What does hol mean in terms of hemoglobin?

Has the two alphas and two betas, as well as 4 hemes

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Hemoglobin forms when one alpha-beta dimer (a protomer) binds to another dimer (protomer). Why is this significant for the conformation?

Allows hemoglobin to switch between two conformations (T and R), each of which have different affinity for oxygen

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Where does oxygen actually bind in hemoglobin?

To heme- at the sixth position on iron

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What molecules have a higher affinity for iron than oxygen?

CO, NO, H2S

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What is the difference between Fe3+ and Fe2+ in terms of oxygen binding?

Only Fe2+(ferro) can bind oxygen

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What is the difference between oxidation state and oxygenation state?

Oxidation state refers to the charge on Fe (if it’s Fe2+ or Fe3+)
Oxygenation state refers to whether or not oxygen is bound to iron
-oxygenation is closely related to oxidation state

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What is metHb?

Ferric (Fe3+) Hb that doesn’t function as an oxygen carrier

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What is the pressure in the atmosphere? Arterial blood? Venous blood?

Atmosphere: 150 atm
Arterial blood: 120 atm
Venous blood: 20 atm

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How do the oxygen dissociation graphs for myoglobin and hemoglobin differ? Why are they different?

Myoglobin is hyperbolic (because non-cooperative), Hemoglobin is sigmoidal (because cooperative binding)

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What is the definition of the P50?

The pressure at which the binding is half maximal or 1/2 of the oxygen has been released

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What are the approximate P50s for hemoglobin and myoglobin?

Hemoglobin: 3 atm (26 torr)
Myoglobin: 2.6 atm

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What are some molecules that favor the T state?

BPG, CO2, H+, Cl-

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A type of allostery where what’s happening at one site promotes the same thing to happen at an identical site, is known as what?

Cooperativity

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In what organs/tissues is the T state favored? The R state?

T state favored in muscles/tissues

R state favored in lungs

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What is the P50 with BPG? What does this mean given the venous blood has a pressure of 20 atm?

26 atm- in venous blood most of the Hb will be unloaded

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Negative effectors that favor the T state cause the oxygen dissociation curve to shift in which direction- left of right?

Right shift

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How does BPG favor the T state?

BPG is acidic and charged and binds to lysine/histidine/ N-termini in beta subunits

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Does the Bohr Effect play a role in both hemoglobin and myoglobin?

No- only in hemoglobin

According to the Bohr effect, when hemoglobin binds oxygen it releases hydrogen ions. How does this effect further binding?

The release of hydrogen is a product, this increasing product leads to more oxygen binding

What is the pH, H+ concentration, and oxygen binding in the lungs?

High pH, low H+, high oxygen binding

What is the pH, [H+], and oxygen binding in muscles?

Low pH, high H+, low oxygen binding

CO2 is made in active tissues as a product. Why is this significant in terms of pH and oxygen saturation?

CO2 combines with H20 to form H2CO3 which then dissociated in H+ and HCO3-; thus H+ is released which decreases the pH and stabilizes the T state

How is the H+ from oxygen binding cleared?

H+ binds with HCO3- and then exhaled as H2O and CO2

What does HbF look like? Does it have an affinity higher or lower than HbA?

Two alphas and two gammas; has a greater affinity for oxygen than HbA

Why does HbF have a greater affinity for oxygen?

Gamma is resistant to BPG, so BPG isn't able to bind and stabilize the T state

What is the mutation in HbS? What chain does it occur on?

Glutamate to valine at position 6 of the beta chain

What happens when there's a mutation that stabilizes methemoglobin?

Get methemoglobinemia- and cyanosis

How does methemoglobinemia lead to cyanosis?

Ferric (3+) Hb can't bind oxygen and any oxygen that is loaded can't be released because the ferric ion moves into the plane with heme

What is the structure of: HbA, HbA2, HbF, HbS, HbC, HbH, and HbBarts

HbA: 2 alpha, 2 beta HbA2: 2 alpha, 2 delta HbF: 2 alpha, 2 gamma HbS: 2 alpha, 2 beta (with a glutamate to valine) HbC: 2 alpha, 2 beta (with a glutamate to lysine) HbH: 4 beta HbBart: 4 gamma

What is the affinity for HbBarts?

Tight and non-cooperative

How are different types of Hb detected?

Natural state gel electrophoresis

What does HbH look like in Asians? Africans?

Asians: both chromosomes can't produce alpha Africans: one chromosome has two alpha knockouts, but the other chromosome has normal Hb

What is the structure of heme? What isomer is found in humans?

porphyrin ring (4 pyrrole rings with a central iron); protoporphyrin IX

How heme A, B, and C different?

A: M, attachment, M, V, M, P, M, P B: M, V, M, V, M, P, M ,P C: M, modified vinyl and attach to cystine, M, P, M, P

What do heme A and B bind to proximally and distally?

Histidine

What step is regulated in heme synthesis? Show the substrates and products

First step | Succinyl CoA + Glycine---> ALA (enzyme ALAS)

What two steps of heme synthesis can be affected by the presence of lead? What enzymes are involved?

Second step: ALA + ALA --> PBG by ALAD because ALAD uses zinc as a cofactor Last step: Proto IX ---> Heme by ferrochelatase

What does lead poisoning cause? How can it be seen in the blood?

Children have developmental problems; seen as a buildup of ALA

What is the last soluble precurser in heme synthesis? What does this mean when there's a problem further down the pathway?

Copro III | A defect further down will show an increase in Copro III

How much energy/ATP goes into making heme?

None

How is heme used in liver cells? When is it needed?

Prosthetic group for cytochrome P450- need when need to detoxify

What are 4 ways in which ALAS can be regulated?

Repress the mRNA, inhibit translation, inhibit the import of ALAS to the mitochondria, directly inhibit ALAS

When is heme synthesis stimulated in liver cells?

When there are toxins/substances that induce cytochrome P450

What are porphyrias? Are they normally heterozygous or homozygous?

Genetic deficiencies in heme synthesis- heterozygous

Those that have congenital erythropoeitic prophyria are deficient in what enzyme? What builds up?

Deficient in uroporphyrinogen III cosynthase | Leads to a buildup of uroporphyrinogen I and copro I

What are the symptoms of erythropoeitic porphyria?

Anemia, skin is photosensitive, red urine, teeth reddish-brown, more hair growth

What enzyme is deficient in those with erythropoeitic porphyria? What do you see a build up of?

Ferrochelatase- see a build up of copro III

What enzyme is deficient in Acute Intermittent Porphyria (AIP)? What accumulates?

PBG deaminase | Accumulation of ALA and PBG

What are the symptoms of Acute Intermittent Porphyria?

Abdominal pain, vomit, diarrhea, neuro dysfunction, red urine

What enzyme is deficient in porphyria cutana tarda? What builds up?

Uroporphrinogen decarboxylase | Build up of uroporphyrinogen III

What parts of hemoglobin are recycled? What parts are just broken down?

Globin component is recycled; heme is just broken down except for the iron which is recycled

What are the three general steps in heme breakdown?

1. breakdown of the porphyrin ring 2. reduction of the broken ring 3. conjugate to sugars to make water soluble

What is the function of heme oxidase? What is the product?

Converts heme into biliverdin; releases CO into the blood

Is bilirubin lipid soluble or water soluble? How does it travel through the blood?

Lipid soluble- has to be attached to albumin to travel through the blood

What does ALA look similar to? Why is this significant with lead poisoning?

GABA; have a build up of ALA with lead poisoning

What color is bilverdin? Bilrubin?

Biliverdin is green; bilirubin is yellow

Before bilirubin can be secreted in the bile it has to be made soluble. How is this achieved?

Conjugation of bilirubin; attach sugars to the bilirubin

Is jaundice really a disease?

No- it's a secondary disease; something else is going on that is causing an abnormal distribution of bilirubin

What causes pre-hepatic jaundice? What would the blood work look like?

Massive breakdown of hemoglobin that the liver can't keep up and conjugate the bilirubin fast enough; get a buildup of unconjugated bilirubin, normal liver function enzymes, no urine bilirubin, but do have urine urobilinogen

What causes intrahepatic jaundice? What would blood work look like?

Diseased condition of the liver; have both conjugated and unconjugated bilirubin, increased liver enzymes, both bilirubin and urobilinogen in the urine

What causes posthepatic jaundice? What would blood work look like?

Blockage of bile out of the liver (gallstone/tumor); buildup of conjugated bilirubin, normal liver enzymes, urine bilirubin present

How is either stored?

As ferritin or hemosiderin

What is the name of the iron transporter?

Transferrin

What is it called when the transferrin releases the iron but remains bound to the receptor in the vesicle?

Apotransferrin