Day 11, Lecture 1: Proteins: Oxygen Transport Proteins Flashcards
The human body requires ____ g of oxygen/day
500g
The gas-binding site: heme prosthetic group is a complex of ___ and ____
- Iron (Fe2+)
- Porphyrin
- (note no amino acid can do the job)
The hemes in the globin protein chains of Hb and Mb are shielded form oxidation by water when hidden inside protein pocket to avoid formation of nonfunctional ______
methemoglobin (MHb)
Why is angled bonding of O2 with heme important
Because of position of the distal histidine residue prevents extremely strong binding of Fe2+ to endogenously produce carbon monoxide
Structure of Myoglobin
- Single polypeptide chain with 153a.a
- compact globular protein with about 80% alpha-helix in 8 segments
- Protein interior is mostly nonpolar amino acids, major stabilization from hydrophobic effect
- surface is mostly polar amino acids, thus highly soluble
- Heme in pocket protected from water
Hemoglobin structure
- 4 subunits (each look like Mb) → 4 Hemes→ 4 oxygens can be bound; 2 alpha subunits and 2 beta subunits
- alpha and beta strongly interact via nonpolar patches to form a alpha-beta dimer. A pair of dimers are held together by ionic and H-bonds.
- Oxygen binding by Hb is variable and depends on the quaternary structure of the Hb tetramer, which in turn depends on its environment
Hb quaternary structure is affect by
- Oxygen concentration/ positive effect at high pO2
- pH/negative effect at low pH
- Carbon dioxide concentration/ negative effect at high concentration
- 2,3-bisphosphoglycerate (BPG or DPG)/ negative effect
- (note that the Mb monomer is not affected by such things) leading to the optimized O2 deliver in the body of 65% rather than the predicted 24-36% of oxygen load if Hb were like Mb.
Define Allosterism
A change in activity induced from a site other than active site
The 4 chains in doxy form of Hb are held toether in part by ___ ionic bonds : called T (taut or tense) form
- 8
- upon oxygen binding a heme:
- The bond between the Fe atom and the coordinating Ns shortens
- Fe is pulled into the plane of the heme group
- The F helix is pulled, and the protein shape changes ot R (relaxed) form (note that the F helix is attached to the proximal histidine)
A structural change within a subunit (heme oxygenation) causes
a structural change at the subunit interface (positive cooperativity)
What is the Bohr effect
- low pH lower’s Hb’s ability to bind O2
- upon oxygenation, protons are released from Hb (pKa changes in R/T forms; loss of ionic bonds)
- Conversely, extra protons (derived form CO2) dissociation and lactic acid/metabolism) will restore ionic bonds thus cause Hb to release O2
- This leads to enhancement of oxygen delivery in tissues at work
CO2 effects of Hb’s ability to bind Oxygen
- CO2 covalently binds to N terminus of Hb chains (creates a negative charge) to form carbamylHb
- Lowers O2 affinity (positive residue interacts with negative carbamate group in an ionic bond → Taut form is stabilized)
- Enhancement of O2 delivery in tissues at work plus removal of some CO2 from tissues (most CO2 by other mechanism)
Effect of BPG on Hb
- Lowers Hb’s ability to bind O2
- Negative-charged BPG participates in an ionic bond network between beta subunits (His, Lys, amino termini) when in Taut deoxy form
- Normally, BPG is found in red blood cells at equimolar concentration (about 5mM) with Hb
- Under hypoxic conditions, such as lung disease, severe anemia, high altitude adaptation, BPG concentration increases (about 8mM) which enhances O2 unloading in tissues
Effect of Carbon monoxide (CO) on Hemoglobin
- breaking down heme generates CO so about 1% CO:Hb in blood is natural
- CO binds Hb 200x more strongly than O2 thus low CO can kill over time
- Brain and heart are most susceptible to hypoxia so most deaths secondary to dysrhythmias and infarction
- CO concentrated by fetus (fetal Hb has higher CO affinity than adult Hb) →low birth weight, wasting, and neurologic deficit.
- Cumulative effect from:
- A bad home furnace or a leaky car exhaust system
- methlene chloride-based paint stripper (liver converts into CO)
- Smoking
