Week 1 Flashcards
Carriers
- Binding proteins & friends
• produced by liver, bone marrow or intestines - Simple & non-specific
• Albumin - Complex & not very specific
• lipoproteins - Complex & very specific
• Haemoglobin
• Hormone-/vitamin-binding proteins
• Transferrin (transport iron)
Albumin
- Main protein of plasma
- Big globular protein
- Produced (+ excocytosed) by liver
- Reversibly binds just about everything
• Cations (Ca2+, Mg2+), free fatty acids, vitamins, hormones, bilirubin, etc
• varying extents (most things are bound by multiple carriers)
Iron
Absorbed in gut, stored in liver, used in bone marrow, and transported between
Iron binding proteins
- Transferrin = transports Fe in blood
- Mobilferrin = transports Fe inside cells
- Ferritin = sequesters Fe inside cells (GIT clearance)
Binding is regulated by Oxidation State
- Reduced Ferrous iron (Fe2+) is water soluble (won’t bind carriers)
- Oxidised Ferric iron (Fe3+) is water insoluble, binds carriers strongly
- Ferroxidase: Fe2+ → Fe3+ (safe storage)
- Ferroductase: Fe3+ → Fe2+ (soluble release)
- Stores/releases iron in a controlled fashion
Hormones
• Many are water soluble
– Adrenaline, DA, insulin, glucagon, FSH, LH, TSH, ANP, SS, CCK, etc.
• Others require carriers
– All steroids (cholesterol-derivatives = lipid)
• Oestrogen/progesterone/testosterone → sex-hormone- binding globulin (SHBG)
• Cortisol/aldosterone → transcortin
– TH
• thyroid hormone-binding globulin (TBG)
Vitamins
• Bs and C – water soluble – dissolved in plasma.
• A, D, E, K all lipid soluble – need a carrier.
– Carried by binding proteins produced in the
liver/intestines
• A: Retinol-binding protein (RBP) & lipoproteins
• D: VDBP (lipoproteins if dietary source)
• E: Lipoproteins, albumins
• K: Lipoproteins
What’s a lipoproteins?
• Lipoprotein complexes carry lipids through circulation
• Distribution and redistribution throughout the body
• Composition
– Apolipoproteins (apoproteins)
– phospholipids
– Triglycerides
– cholesterol, cholesteryl esters.
What are the 3 classes of Lipoproteins(LP)?
- Chylomicrons (CMs)
- Low density LPs (LDLs)
- High density LPs (HDLs)
Chylomicrons (CMs)
– Produced in gut – loaded with dietary lipids
– Distribute lipids to rest of body
– Taken up by liver (as CMRs)
Low density LPs (LDLs)
– Produced in liver (VLDL)
– Loaded with liver lipids
– Distribute lipids to rest of body
– Taken up by liver
High Density LPs (HDLs)
– Produced in liver – but empty!
– Pick up cholesterol from rest of body → dump in liver (reverse cholesterol transport)
LP unloading
• 2 ways to remove lipids from blood
- Unload lipids from the lipoprotein
– Enzyme-catalysed removal of lipids from LPs
• TGs - requires lipoprotein lipase enzyme (LPL) - Remove the entire lipoprotein!
– Endocytosis of LP complex (liver, mostly)
• Requires lipoprotein receptors (LPRs) (HDLs via SRB1)
• Lipoprotein lipase enzyme
– Found on muscle, adipose tissue, heart, mammary glands – Liberates FFAs from TGs, FFAs are then removed from LPs.
Apolipoproteins (apoproteins)
• Dictate the fate of lipoproteins!
– ligands for cell-surface receptors (destination).
• apoB – required for cellular uptake of CMs & LDLs
– Enzyme cofactors (regulate activity)
• apoCII – required for unloading FAs (LPL-cofactor)
• apoA1 – required for loading C into HDLs (ABCA1-cofactor)
• Apoprotein cofactors are recycled between circulating LPs (they literally play swappsies)
Gas Transport
- gas exchange via passive diffusion and always down a concentration gradient
- lungs = High O2, low CO2 (O2 will enter blood, CO2 will leave blood
- tissues = Low O2, high CO2 (O2 will leave blood, CO2 will enter blood
Diffusion
• O2 and CO2 are easily able to cross cell membranes and are soluble in aqueous solution
Henry’s Law
When a mixture of gases is in contact with a liquid, each gas will dissolve in the liquid in proportion to its partial pressure
• At equilibrium, partial pressures in alveoli (A) and capillaries (a) will be equal
• A-a gradient determines direction of diffusion
CO2 is 20 times more soluble in water than O2
How many mmHg of O2 do you breathe in?
160 mmHg to 100 mmHg
How many mmHg of CO2 do you breathe in?
0.3 mmHg to 40 mmHg
Haemoglobin
• Produced by maturing RBCs
• 4 subunits each consisting of
– Globin (polypeptide) chains
– HbA: 2x α-globin & 2x β-globin
– Haem unit (1x Fe2+ & 1x protoporphyrin molecule)
• O2 binds loosely & reversibly to Fe2+ of Hb
– Co-ordination bonds
Oxygen Transport with Haemoglobin
– O2 binds reversibly to haemoglobin (Hb) in RBC
– 1 g Hb can bind 1.39 mL O2
• ♂ [Hb] 150 g/L = 208.5 mL/L O2 (70x plasma [O2])
Loading and unloading of O2 is still entirely passive
– Dependent upon [O2] gradient
PCO2 = the Bohr effect!
• Increased PCO2 reduces how tightly Hb binds O2
• Hb dumps more O2 in hypercapnic (= metabolically -active) tissues
Increased Hb O2 release
- High DPG
• Glycolysis intermediate; accumulates in RBCs under
hypoxic conditions - Acidosis
• CO2 , lactic acid - High temperature
• high metabolism, muscular contraction - More O2 gets dumped in metabolically active +/or hypoxic tissues!
Other globins
• Myoglobin (Mb)
– O2-binding protein in red muscles
– Cytoplasmic in muscle (no transport)
– Single haem-Fe group (not 4)
• Fetal Haemoglobin (HbF)
– 6 week fetal → 3 mo post partum
– 4 haem-Fe groups
• two α (alpha) subunits and two γ (gamma) subunits
CO2?
• Much more soluble (~22x) in plasma/cytoplasm than O2.
• But, we can increase transport efficiency if we load it into RBCs.
• Carbon dioxide transport:
– Carbonic anhydrase in RBC catalyses the reaction
CO2 + H2O ⇌ H2CO3 ⇌ H+ + HCO3–
– Hb in RBC (and proteins in plasma) bind CO2 forming carbamino compounds
CO2 Transport
Dissolved CO2 (~10%)
– ~22x more soluble than O2 - a significant fraction of total transport.
• Carbamino (~20%)
– CO2 combines with terminal amino groups of proteins (haemoglobin)
– R-NH2 + CO2 ↔ R-NHCOO- + H+
– CO2 and O2 bind separate parts of haemoglobin.
• Bicarbonate (~70%)
– Most CO2 in blood carried as bicarbonate
– CO2+H2O ↔ H2CO3 ↔ H+ +HCO3-
• Slow in plasma, 5000x faster in RBC (contain carbonic anhydrase).
• Diffuse (facilitated) out of RBCs (Cl- shift – more Cl- in venous RBCs)
Acid-Base Homeostasis
- ECF [H+] = 40 nEq/L (normal [H+] = ±3-5 nEq/L)
- pH= -log[H+] = 7.4
Acidosis (process), Acidaemia (state)
- increase in acidity ([H+]) of body fluids
- reduction in arterial pH <7.45
Alkalosis (process), Alkalaemia (state)
- reduction in acidity ([H+]) of body fluids
- increase in arterial pH >7.45
What effect does pH have on metabolism?
- every step of metabolic process is pH dependant
- deviate from optimal pH = decrease in rxn efficiency
- why? Enzymes
What effect does ph have on the neuromuscular system?
- Acidosis = inhibitory and Alkalosis = excitatory
- Acidosis increases free plasma [Ca2+]
• Ca2+ binding to albumin is pH dependent
• Ca2+ blocks vNa+ channels which raises AP threshold - K+ balance:
• Acidosis causes increases in serum [K+]
• Alkalosis causes decreases in serum [K+]
Consequences of Acidosis
- headaches, confusion, lethargy, tremors, sleepiness
- cerebral dysfunction causing coma
- hyperventilation
Consequences of Alkalosis
- muscular weakness, pain, cramps, spasms (smooth and skeletal muscle) causing tetany
- hypoventilation
Defence mechanisms: Chemical buffering
Immediate but exhaustible
- solutions that resist changes in pH
- intracellular and extracellular buffers provide an immediate response to acid-base disturbances (bone also buffers acid loads)
Defence mechanism: Pulmonary regulation
- [CO2] is regulated by changes in breathing frequency & depth
- As CO2 is exhaled, blood pH increases
Defense mechanism: Renal regulation
- kidneys control & adjust the amount of HCO3- and/or H+ that is excreted
- excreting HCO3- decreases blood pH
- excreting H+ increases blood pH
Buffer Systems
- Buffer = substance that reversibly consumes or releases H+ to ↓changes in pH
- made up of weak acid and its conjugate base
• conjugate base can accept H+ and the weak acid can donate H+ which minimises changes in free [H+] - Buffer + H+ ⇌ H-Buffer
