HemoglobinandtheMovementof*Oxygenoregonstate.edu/instruct/bb450/450material/Keynotes... ·...

Hemoglobin and the Movement of Oxygen

Hemoglobin and the Movement of Oxygen• Introduction


Animals Have Widely Varying Needs for OxygenDemand for Oxygen Can Change in SecondsBasal Needs are Significant - Diffusion not Enough


Animals Have Widely Varying Needs for OxygenDemand for Oxygen Can Change in SecondsBasal Needs are Significant - Diffusion not EnoughExercise, Fight/Flight Add to the Need


Animals Have Widely Varying Needs for OxygenDemand for Oxygen Can Change in SecondsBasal Needs are Significant - Diffusion not EnoughExercise, Fight/Flight Add to the NeedATP Energy Produced Aerobically 15 Times More Efficiently Than Anaerobically



Respiration versus Fermentation



Respiration versus FermentationEfficient, Adaptable Oxygen Delivery is Necessary

Quaternary Structure• Interaction of multiple protein subunits


Hemoglobin - 4 Subunits (α2β2), 1 Heme Each, 1 O2 Each, 1 “Donut Hole”Myoglobin - 1 Subunit, 1 Heme, 1 O2 Each

















Hemoglobin and the Movement of Oxygen• Structure and Function


Heme Prosthetic GroupFerrous Iron - Methemoglobin Won’t WorkOnly Fe++ Binds Oxygen



Edge-on View


Edge-on View

Attached to Remainder of Global Subunit


Edge-on View



Edge-on View


Histidine’s Movement Changes

Global Unit’s Shape

Hemoglobin and the Movement of Oxygen• Cooperativity

Exiting Lungs


Entering Lungs

Exiting Lungs


No Oxygen (T-State)

Entering Lungs

Exiting Lungs


No Oxygen (T-State)

Oxygen Bound

Entering Lungs

Exiting Lungs


No Oxygen (T-State)

Oxygen Bound

Affected by O2 Binding (R-State)

Entering Lungs

Exiting Lungs


No Oxygen (T-State)

Oxygen Bound Affected by O2 Binding

R-State


Entering Lungs

Exiting Lungs


No Oxygen (T-State)


R-State


Entering Lungs

Exiting Lungs

Fully Oxygenated (R-State)


No Oxygen (T-State)


R-State


Binding of the first O2 favors binding of second, etc. - CooperativelyCooperatively Important as Hemoglobin Rapidly Passes Through Lungs

Entering Lungs

Exiting Lungs

Fully Oxygenated (R-State)



At Low O2, Myoglobin Holds More than Hemoglobin







At High O2, Both Hold 100%




Hyperbolic Binding Curve




Sigmoidal Binding Curve

Hyperbolic Binding Curve




As Curves Move to Right Less Affinity for Oxygen




Myoglobin Better for Storing OxygenHemoglobin Better at Delivering Oxygen

As Curves Move to Right Less Affinity for Oxygen

Hemoglobin and the Movement of Oxygen• Bohr Effect


Less Oxygen Bound at Same Pressure


Less Oxygen Bound at Same Pressure

More O2 Required To Have Same Fraction Bound


More Affinity


More Affinity

Less Affinity


Protons Can Bind to HemoglobinProtons Change Hemoglobin’s Shape Reshaped Hemoglobin Loses Oxygen



Rapidly Metabolizing Tissues Release Protons



Rapidly Metabolizing Tissues Release ProtonsRapidly Metabolizing Tissues Get More Oxygen From Hemoglobin

Hemoglobin and the Movement of Oxygen• Bohr Effect & CO2



Acid Favors Release of O2 From HemoglobinCO2 Favors Release of O2 From Hemoglobin


Acid Favors Release of O2 From HemoglobinCO2 Favors Release of O2 From Hemoglobin

Acid and CO2 are Released by Rapidly Metabolizing Tissues

Hemoglobin and the Movement of Oxygen• 2,3 BPG

2,3 Bisphosphoglycerate



Byproduct of GlycolysisExercising Muscle Cells Rapid Use GlycolysisExercising Muscle Cells Produce Acid, CO2, and 2,3 BPG



Byproduct of GlycolysisExercising Muscle Cells Rapid Use GlycolysisExercising Muscle Cells Produce Acid, CO2, and 2,3 BPGBinds in Hole of Donut



Byproduct of GlycolysisExercising Muscle Cells Rapid Use GlycolysisExercising Muscle Cells Produce Acid, CO2, and 2,3 BPGBinds in Hole of DonutLocks Hemoglobin in T-State

Hemoglobin and the Movement of Oxygen• 2,3 BPG and Oxygen Binding


Slow Metabolic Rate


Slow Metabolic Rate

Fast Metabolic Rate



Rapidly Metabolizing Cells Produce AcidRapidly Metabolizing Cells Release CO2



Rapidly Metabolizing Cells Release 2,3 BPG




All Favor O2 Release from Hemoglobin




All Favor O2 Release from Hemoglobin So




All Favor O2 Release from Hemoglobin So

Rapidly Metabolizing Cells Get More O2

Hemoglobin and the Movement of Oxygen• 2,3 BPG and Smoking




2,3 BPG Big Concern for SmokersBlood of Smokers has High Levels of 2,3 BPGHemoglobin Gets Locked in T-state in Passage Through Lungs



2,3 BPG Big Concern for SmokersBlood of Smokers has High Levels of 2,3 BPGHemoglobin Gets Locked in T-state in Passage Through LungsOxygen Carrying Capacity of Blood Reduced



2,3 BPG Big Concern for SmokersBlood of Smokers has High Levels of 2,3 BPGHemoglobin Gets Locked in T-state in Passage Through LungsOxygen Carrying Capacity of Blood ReducedCarbon Monoxide Levels Also Higher in Smokers

Hemoglobin and the Movement of Oxygen• Movement of CO2


Rapidly Metabolizing Tissue



HbO + H+ O2 Blood



H+:Hb-CO2

HbO + H+ O2 Blood


Rapidly Metabolizing Tissue Some

H+:Hb-CO2

HbO + H+ O2 Blood



H+:Hb-CO2

RemainderH2O

Blood

HbO + H+ O2 Blood



H+:Hb-CO2

RemainderH2O

Blood

HbO + H+ O2 Blood

H+:Hb-CO2

HbO



LungsO2 + H+:Hb-CO2

H+:Hb-CO2

RemainderH2O

Blood

HbO + H+ O2 Blood

H+:Hb-CO2

HbO



LungsO2 + H+:Hb-CO2

H+:Hb-CO2

RemainderH2O

Blood

HbO + H+ O2 Blood

H+:Hb-CO2

HbO HbO



LungsO2 + H+:Hb-CO2

H+:Hb-CO2

RemainderH2O

Blood

HbO + H+ O2 Blood

H+:Hb-CO2

HbO HbO



H2O + CO2 LungsO2 + H+:Hb-CO2

H+:Hb-CO2

RemainderH2O

Blood

HbO + H+ O2 Blood

H+:Hb-CO2

HbO HbO



H2O + CO2 LungsO2 + H+:Hb-CO2

H+:Hb-CO2

RemainderH2O

Blood

HbO + H+ O2 Blood

H+:Hb-CO2

HbO HbOExhaled

Hemoglobin and the Movement of Oxygen• Carbon Monoxide and Heme


An Additional Histidine is Present at the Heme Iron SiteReduces Affinity to CO, but Does Not Eliminate itCarbon Monoxide in Cigarette Smoke


An Additional Histidine is Present at the Heme Iron SiteReduces Affinity to CO, but Does Not Eliminate itCarbon Monoxide in Cigarette SmokeNote That CO2 Does Not Bind to Heme, nor do Protons

Hemoglobin and the Movement of Oxygen• Fetal Hemoglobin


The Body Makes Different Globins Over TimeMost Variations Centered on BirthFetal Hemoglobin Mostly α2γ2



High Most of Life



High Most of Life

Highest in Fetus



High Most of Life

Highest in Fetus At Adult Levels by 24 Weeks


Increasing Affinity

Fetal Hemoglobin Can’t Bind to 2,3 BPG Mostly Remains in R-state

Hemoglobin and the Movement of Oxygen• Sickle Cell Anemia


Sickle Cell Anemia is a Genetic Disease Affecting HemoglobinMultiple Forms - Mutation of Glu to Val at Position #6 Most CommonRed Blood Cells Lose Rounded Shape and Form Sickles


Sickle Cell Anemia is a Genetic Disease Affecting HemoglobinMultiple Forms - Mutation of Glu to Val at Position #6 Most CommonRed Blood Cells Lose Rounded Shape and Form SicklesShape Change Happens in Low O2 Conditions - Exercise


Sickle Cell Anemia is a Genetic Disease Affecting HemoglobinMultiple Forms - Mutation of Glu to Val at Position #6 Most CommonRed Blood Cells Lose Rounded Shape and Form SicklesShape Change Happens in Low O2 Conditions - ExerciseChange Caused by Polymerization of Hemoglobin


Sickle Cell Anemia is a Genetic Disease Affecting HemoglobinMultiple Forms - Mutation of Glu to Val at Position #6 Most CommonRed Blood Cells Lose Rounded Shape and Form SicklesShape Change Happens in Low O2 Conditions - ExerciseChange Caused by Polymerization of Hemoglobin

Sickled Cells



Rounded Cells Move Easily Through Capillaries

Sickled Cells Get Stuck



Sickled Cells Get Stuck



Sickled Cells Get StuckSickled Cells Removed by Spleen



Why is Sickle Cell Anemia so Widespread?Why Has it Not Been Selected Against?





Greatest Incidence of Sickle Cell Anemia



Greatest Incidence of MalariaGreatest Incidence of Sickle Cell Anemia



Greatest Incidence of MalariaGreatest Incidence of Sickle Cell Anemia


Benefit of Sickle Cell Mutation for Heterozygotes No Benefit to Homozygous Recessive or Dominant

Hemoglobin and the Movement of Oxygen• Summary


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different Functions


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of Each


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s Shape


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s ShapeChanging Hemoglobin’s Shape Converts Hemoglobin from T-state to R-state


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s ShapeChanging Hemoglobin’s Shape Converts Hemoglobin from T-state to R-stateR-state Binds Oxygen Better. T-state Releases O2 Better


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s ShapeChanging Hemoglobin’s Shape Converts Hemoglobin from T-state to R-stateR-state Binds Oxygen Better. T-state Releases O2 BetterIn the Bohr Effect, Binding of CO2 and H+ Favors O2 Release


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s ShapeChanging Hemoglobin’s Shape Converts Hemoglobin from T-state to R-stateR-state Binds Oxygen Better. T-state Releases O2 BetterIn the Bohr Effect, Binding of CO2 and H+ Favors O2 ReleaseThe Bohr Effect Explains How Oxygen and CO2 Exchanged in Lungs


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s ShapeChanging Hemoglobin’s Shape Converts Hemoglobin from T-state to R-stateR-state Binds Oxygen Better. T-state Releases O2 BetterIn the Bohr Effect, Binding of CO2 and H+ Favors O2 ReleaseThe Bohr Effect Explains How Oxygen and CO2 Exchanged in Lungs2,3 BPG is Produced by Rapidly Metabolizing Cells. It too Favors O2 Release


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s ShapeChanging Hemoglobin’s Shape Converts Hemoglobin from T-state to R-stateR-state Binds Oxygen Better. T-state Releases O2 BetterIn the Bohr Effect, Binding of CO2 and H+ Favors O2 ReleaseThe Bohr Effect Explains How Oxygen and CO2 Exchanged in Lungs2,3 BPG is Produced by Rapidly Metabolizing Cells. It too Favors O2 ReleaseFetal Hemoglobin Can’t Bind 2,3 BPG and has Greater O2 Affinity Than Adult Hemoglobin


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s ShapeChanging Hemoglobin’s Shape Converts Hemoglobin from T-state to R-stateR-state Binds Oxygen Better. T-state Releases O2 BetterIn the Bohr Effect, Binding of CO2 and H+ Favors O2 ReleaseThe Bohr Effect Explains How Oxygen and CO2 Exchanged in Lungs2,3 BPG is Produced by Rapidly Metabolizing Cells. It too Favors O2 ReleaseFetal Hemoglobin Can’t Bind 2,3 BPG and has Greater O2 Affinity Than Adult HemoglobinSickle Cell Anemia (SCA) is a Genetic Disease of Hemoglobin


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s ShapeChanging Hemoglobin’s Shape Converts Hemoglobin from T-state to R-stateR-state Binds Oxygen Better. T-state Releases O2 BetterIn the Bohr Effect, Binding of CO2 and H+ Favors O2 ReleaseThe Bohr Effect Explains How Oxygen and CO2 Exchanged in Lungs2,3 BPG is Produced by Rapidly Metabolizing Cells. It too Favors O2 ReleaseFetal Hemoglobin Can’t Bind 2,3 BPG and has Greater O2 Affinity Than Adult HemoglobinSickle Cell Anemia (SCA) is a Genetic Disease of HemoglobinIn Low O2 Concentration, Red Blood Cells of SCA Sufferers Form Sickle Shapes


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s ShapeChanging Hemoglobin’s Shape Converts Hemoglobin from T-state to R-stateR-state Binds Oxygen Better. T-state Releases O2 BetterIn the Bohr Effect, Binding of CO2 and H+ Favors O2 ReleaseThe Bohr Effect Explains How Oxygen and CO2 Exchanged in Lungs2,3 BPG is Produced by Rapidly Metabolizing Cells. It too Favors O2 ReleaseFetal Hemoglobin Can’t Bind 2,3 BPG and has Greater O2 Affinity Than Adult HemoglobinSickle Cell Anemia (SCA) is a Genetic Disease of HemoglobinIn Low O2 Concentration, Red Blood Cells of SCA Sufferers Form Sickle ShapesSickled Cells Stick in Capillaries and Can be Fatal


Animals Have Widely Varying O2 NeedsATP Generated Much More Efficiently in Presence of O2Hemoglobin and Myoglobin are Related, but Have Different FunctionsHemoglobin has Four Subunits and Hemes. Myoglobin has One of EachBind of O2 by Heme’s Iron Pulls up on a Histidine and Change’s Hemoglobin’s ShapeChanging Hemoglobin’s Shape Converts Hemoglobin from T-state to R-stateR-state Binds Oxygen Better. T-state Releases O2 BetterIn the Bohr Effect, Binding of CO2 and H+ Favors O2 ReleaseThe Bohr Effect Explains How Oxygen and CO2 Exchanged in Lungs2,3 BPG is Produced by Rapidly Metabolizing Cells. It too Favors O2 ReleaseFetal Hemoglobin Can’t Bind 2,3 BPG and has Greater O2 Affinity Than Adult HemoglobinSickle Cell Anemia (SCA) is a Genetic Disease of HemoglobinIn Low O2 Concentration, Red Blood Cells of SCA Sufferers Form Sickle ShapesSickled Cells Stick in Capillaries and Can be FatalPeople Heterozygous for the Mutated Gene Survive Malaria Better Than Others

Protein Structure

Primary -‐ Sequence of amino acidSecondary -‐ Interaction of amino acids close in primary sequenceTertiary -‐ Interaction of amino acids distantly located

Protein Structure

Primary -‐ Sequence of amino acidSecondary -‐ Interaction of amino acids close in primary sequenceTertiary -‐ Interaction of amino acids distantly locatedQuaternary -‐ Interaction of protein subunits

Protein Structure

Metabolic Melody

Oh isn't it greatWhat proteins can do

Especially ones that bind to O2Hemoglobin's moving around

Inside of the lungs It picks up the bait

And changes itself from T to R state Hemoglobin's moving around

The proto-porphyrin system Its iron makes such a scene Arising when an O2 binds

Pulling up on histidine

The binding occurs Cooperatively

Thanks to changes qua-ter-nar-y Hemoglobin's moving around

It exits the lungs Engorged with O2

In search of a working body tissue Hemoglobin's moving around

Hemoglobin's Moving Around (To the tune of "Santa Claus is Coming to Town")

Copyright © Kevin Ahern

http://www.davincipress.com/professional.html

Oh isn't it greatWhat proteins can do

Especially ones that bind to O2Hemoglobin's moving around

Inside of the lungs It picks up the bait

And changes itself from T to R state Hemoglobin's moving around

The proto-porphyrin system Its iron makes such a scene Arising when an O2 binds

Pulling up on histidine

The binding occurs Cooperatively

Thanks to changes qua-ter-nar-y Hemoglobin's moving around

It exits the lungs Engorged with O2

In search of a working body tissue Hemoglobin's moving around

Hemoglobin's Moving Around (To the tune of "Santa Claus is Coming to Town")


The proton concentration Is high and has a role

Between the alpha betas It finds imidazole

To empty their loads The globins decree

"We need to bind 2,3BPG" Hemoglobin's moving around

The stage is thus setFor grabbing a few

Cellular dumps of CO2Hemoglobin's moving around

And then inside the lungs it Discovers ox-y-gen

And dumps the CO2 off To start all o'er again

So see how this works You better expect

To have to describe the Bohr effect Hemoglobin's moving around


Metabolic Melody

The Bloody Things(To the tune of “Coke ® It's The Real Thing”)





I’m gonna put some oxygensbeside my porphyrin rings

To nudge the irons up a notchand yank on histidines

The globins’ shapes will change a bit,oh what a sight to see

The way they bind to oxygenco-op-er-AH-tive-ly

And as I exit from the lungsto swim in the bloodstreamMetabolizing cells they allexpress their needs to meTo them I give up oxygenand change from R to T

While my amines, they hang ontothe protons readily




I’m gonna put some oxygensbeside my porphyrin rings

To nudge the irons up a notchand yank on histidines

The globins’ shapes will change a bit,oh what a sight to see

The way they bind to oxygenco-op-er-AH-tive-ly

And as I exit from the lungsto swim in the bloodstreamMetabolizing cells they allexpress their needs to meTo them I give up oxygenand change from R to T

While my amines, they hang ontothe protons readily

But that's not all the tricks I know,there's more that’s up my sleeve

Like gaps between sub-U-nits thathold 2,3-BPG

When near met-a-bo-LI-zing cells,I bind things that diffuse

The protons and bicarbonatesfrom lowly cee oh twos

CHORUS

That’s the way it isWhen your cells are at play

Go say hip hip hoorayFor the bloody things


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HemoglobinandtheMovementof*Oxygenoregonstate.edu/instruct/bb450/450material/Keynotes... ·...