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360 Cards in this Set
- Front
- Back
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What can make FA's? |
- phospholipids - TAG's |
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What can make glucose? |
- starch - glycogen - sucrose |
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what can make pyruvate? |
- alanine - glucose - serine |
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what can make acetate (acetyl CoA)? |
- isoleucine - leucine - pyruvate - phenylalanine - FA's |
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What do rates of biochemical pathways depend on? |
activities of enzymes that catalyze each step - enzyme can be modified by many different mechanisms |
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What kind of reaction is the following? BBBBBBBBB ------------> C |
Enzyme-limited reaction |
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What kind of reaction is the following? C ------------> D |
Substrate limited |
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How many enzyme-limited steps are in metabolic pathways? |
- more or equal to/than 1 |
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What kind of heat is released during rate-limiting steps? |
exergonic |
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True or False? Are rate-limiting steps are irreversible |
True! |
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What kind of regulation controls enzymes which catalyze exergonic, rate-limiting steps? |
metabolic regulation |
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Which enzymes are rate-limiting in glycolysis? |
- hexokinase - phosphofructokinase-1 - pyruvate kinase |
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What is the preparatory phase of glycolysis? |
Phosphorylation of glucose and its conversion to glyceraldehyde 3-phosphate |
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What is the "payoff phase" of glycolysis? |
oxidative conversion of glyceraldehyde 3-phosphate to pyruvate and the coupled formation of ATP and NADH |
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Which rate-limiting enzymes from glycolysis are allosterically inhibited by its product? |
- hexokinase - pyruvate kinase |
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What are the hexokinase enzymes called in the liver/muscle? |
Liver: hexokinase IV (glucokinase) Muscle: Hexokinase I |
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What do we call enzymes that have the same substrate and product but sequences of the enzymes aren't identical therefore the way they are regulated isn't identical? |
isozymes |
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What product inhibits hexokinase I? |
G 6-P |
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Which hexokinase (muscle or liver) has lower affinity for glucose? |
liver |
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What is hexokinase IV inhibited by? |
F 6-P (through glucokinase regulatory protein) **NOT ACTING AS ALLOSTERIC INHIBITOR |
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What enzyme commits F 6-P to glycolysis? |
Phosphofructokinase-1 (PFK-1) |
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What binds to allosteric site on PFK-1 to lower its affinity for F 6-P? |
ATP |
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What relieves inhibition of ATP on PFK-1? |
- ADP - AMP |
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What is a strong activator of PFK-1? |
F 2,6-BP |
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What increases the inhibition by ATP on PFK-1? |
- citrate |
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Which step does pyruvate kinase catalyze? |
Phosphoenolpyruvate (PEP) ---> pyruvate (last step in glycolysis) |
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When [ATP] allosterically inhibits pyruvate kinase, what is decreased? |
pyruvate kinase's affinity for phosphoenolpyruvate (PEP) |
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What inhibits pyruvate kinase? |
- citrate - Acetyl-CoA - Long-chain FA's - ATP - Alanine |
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what are the main precursors of glucose? |
- lactate - pyruvate - glycerol |
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what can glucose 6-phosphate be turned into? |
- blood glucose - glycogen - glycoproteins - disaccharides - other monosaccharides - starch - sucrose |
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Whats one advantage to the mitochondrial bypass to PEP in gluconeogenesis? |
avoids depleting NADH in the cytosol |
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In what tissues is glucose 6-phosphatase expressed in? |
- liver - kidney - small intestine |
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What are the two inhibitors of Fructose 1,6- Bisphosphatase? |
- Fructose 2,6- Bisphosphate - AMP |
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What molecule is a key regulator of glycolysis and gluconeogenesis? |
F 2,6-BP - inhibits Fructose 1,6-Bisphosphatase - encourages PFK-1 |
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What is an activator and inhibitor of pyruvate carboxylase? |
- acetyl-CoA (+) - ADP (-): sign that theres lack of energy so not going to make glucose if cell doesnt have a lot of energy |
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What is an inhibitor of PEP carboxykinase? |
- ADP |
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How does F 2,6-BP regulate PFK-1 and Fructose 1,6- Bisphosphatase? |
allosterically in a reciprocal manner |
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What is [F 2,6-BP] controlled by? |
- phosphofructokinase-2 (PFK-2) makes it - Fructose 2,6-bisphosphatase (FBPase-2) breaks it down |
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Which bifunctional enzyme is regulated by: - hormone-controlled phosphorylation (PKA) - xylulose 5-phosphate |
phosphofructokinase-2 / Fructose 2,6-BPase |
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what does phosphorylation on Ser 32 activate? |
FBPase-2 in the bifunctional enzyme PFK2/FBPase-2 in the LIVER |
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What does phosphorylation on Ser 406 and Thr 475 activate? |
PFK-2 in the bifunctional enzyme PFK2/FBPase-2 in the cardiac muscle! |
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What are the two phases of the pentose phosphate pathway? |
1. Oxidative oxidation of G 6-P ---> NADPH + ribose 5-P 2. Non-oxidative isomerization/rearrangements |
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What is the modulator of phosphatase that stimulates liver PFK-2? |
xylulose 5-phosphate |
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what are the reasons for the oxidative phase of the pentose phosphate pathway? |
- for the synthesis of nucleotides (ribose 5-P) - reductive biosynthesis (NADPH), for example: FA's |
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What are the reasons for the non-oxidative phase of the pentose phosphate pathway? |
- replenish G 6-P and glycolytic intermediates - source of xylulose 5-P |
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Glucose 6-phosphate dehydrogenase regulates which pathway? |
pentose phosphate pathway |
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What is glucose 6-phosphate dehydrogenase stimulated and inhibited by? |
- stimulated by NADP+ - inhibited by NADPH |
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What phosphorylates (activates) glycogen phosphorylase? |
glycogen phosphorylase b kinase |
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What dephosphorylates (inhibits) glycogen phosphorylase? |
glycogen phosphorylase a phosphatase |
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The activity of glycogen phosphorylase b kinase is stimulated by what? |
PKA-mediated phosphorylation |
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What lacks glucagon receptors? |
myocytes |
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True or False Muscle pyruvate kinase is phosphorylated by PKA |
FALSE! Muscle pyruvate is NOT phosphorylated by PKA |
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What enzymes do muscles lack? |
gluconeogenic |
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What part of the body lacks a key enzyme for glucose export? |
muscles |
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What protein coats lipid droplets/adipocytes? |
perilipin |
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Where does FA degradation occur? |
in the mitochondria |
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What is the role of perilipin? |
coats lipid droplets, protecting them from lipases until phosphorylated |
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Lists the steps of mobilization of FA's from adipocytes |
1. glucagon indirectly activates PKA 2. PKA phosphorylates and activates hormone sensitive lipase (HSL) and perilipin 3. Phosphorylated perilipin releases the protein CGI and also allows lipases access to the lipid droplet 4. Adipocyte triacyl glycerol lipase (ATGL) is the lipase which releases the first FA from TAG once activated by released CGI 5. HSL cleaves the 2nd FA from diacyl glycerol 6. Monoacyl glycerol lipase (MGL) cleaves the 3rd FA from monoacyl glycerol 7. Released FA's enter the bloodstream where they bind to serum albumin 8. FA transporter in the muscle cell takes up FA 9. FA will then be oxidized in the muscle cell via beta oxidation |
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whats the most common protein in your blood? |
serum albumin |
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where does beta oxidation of FA's occur? |
in the mitochondria |
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When is a carnitine shuttle needed? |
When FAs are equal to or bigger than 14 C |
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What enzyme converts cytoplasmic FAs to fatty acyl-CoA before theyre transported into mitochondria? |
acyl CoA synthetase |
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List the steps of how FAs enter the mitochondria |
1. cytoplasmic FAs ---> fatty acyl-CoA enzyme: acyl CoA synthetase 2. Fatty acyl group is then transferred to carnitine by carnitine acyltransferase I 3. Fatty acyl-carnitine enters mitochondria via acyl-carnitine/carnitine transporter 4. Fatty acyl-CoA regenerated within the mitochondrion by carnitine acyltransferase II |
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What transporter allows acyl-carnitine entry into the matrix of the mitochondria? |
acyl-carnitine/carnitine transporter |
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Whats the rate-limiting step of the carnitine shuttle? |
transferring the fatty acyl-carnitine into the mitochondria ***Once its in it can't go back and now its dedicated to being oxidized |
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List the three stages of complete oxidation of FAs |
1. Beta oxidation produces acetyl CoA 2. Acetyl CoA is oxidized in the citric acid cycle 3. NADH & FADH2 donate e- to mitochondrial respiratory chain, ultimately yielding ATP |
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What does beta oxidation do? |
converts FA's to acetyl-CoA
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What does one cycle of beta oxidation result in |
one acetyl-CoA being removed from the carboxyl end of the FA chain |
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How many carbon atoms are removed through each pass of the beta oxidation cycle? |
2 |
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When does the beta oxidation process come to a stop? |
when there only acetyl-CoA left |
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How many ATP can be produced from complete oxidation of C16-CoA? |
~108 ATP |
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List the three problem cases for FA degradation |
1. FAs with odd number of C's 2. FAs with cis double bonds 3. FAs with two double bonds |
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What happens in FA degradation if there is an uneven number of carbons? |
- beta oxidation initially proceeds normally - Propionyl-CoA (3 C atoms) cannot be oxidized by acyl-CoA dehydrogenase - There is a separate 3 enzyme pathway that carboxylates propionyl-CoA to the 4 C molecule, succinyl-CoA (part of TCA) |
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What happens in FA degradation if there is a cis double bond in the FA? |
- beta oxidation enzymes process the FA normally as long as the cis double bond isnt at C2 or C3 - bond is brought to C3. cis-delta3 is not a substrate for acyl-CoA dehydrogenase bc C3 is already in a double bond - the enzyme Δ3,Δ2-enoyl-CoAisomerase can move the double bond - It converts the cis-Δ3 FA totrans-Δ2 - trans-Δ2 FA is a substrate forenoyl-CoA hydratase - β-oxidation therefore canproceed normally - The net result is that weproduce one fewer FADH2(because acyl-CoAdehydrogenase skipped this cycle). |
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Which intermediate in the TCA cycle can be put through gluconeogenesis to make glucose? |
oxaloacetate |
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What allows acetyl-CoA to enter the citric acid cycle in a different cell than degraded the FA? |
ketone bodies |
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What can acetyl-CoA in the liver be turned into instead of being degraded in the TCA? |
ketone bodies |
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when a ketone body is formed, what three things can acetyl-CoA become? |
Acetoacetate D-B-hydroxybutyrate acetone |
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How is acetoacetate formed? |
condensing 3 acetyl-CoA molecules, then cleaving one |
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What is the key metabolite in the formation of acetoacetate? |
β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) |
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What is formed when acetoacetate is reduced? |
D-β-hydroxybutyrate |
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What is a minor product formed by acetoacetate during decarboxylation? |
acetone |
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Where does FA biosynthesis take place? |
in the cytoplasm |
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What is the committed step in FA biosynthesis? |
Acetyl-CoA conversion to malonyl-CoA |
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How is citrate produced? |
mitochondrial acetyl-CoA is combined with oxaloacetate |
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what does citrate lyase produce? |
acetyl-CoA in the cytosol |
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What activated intermediate are FAs made from? |
malonyl-CoA |
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What is malonyl-CoA made from? in what kind of reaction? catalysed by what enzyme? |
acetyl-CoA and HCO3 in an ATP dependent reaction catalysed by acetyl-CoA carboxylase |
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What protein carries the biotin cofactor? |
biotin carrier protein |
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Which enzyme uses ATP to activate biotin with CO2? |
biotin carboxylase |
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what is the purpose of transcarboxylase? |
transfers CO2 from biotin to acetyl-CoA to form malonyl-CoA |
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What is the four step sequence to FA biosynthesis? |
- condensation of malonyl-CoA with growing FA - keto reduction - dehydration - enoyl reduction |
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What is the reducing agent for the reductions that take place in FA biosynthesis? |
NADPH |
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What small protein is the FA covalently attached to in FA biosynthesis? |
Acyl carrier protein (ACP) |
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What is the FA synthase organization in vertebrates? |
KS---MAT---DH---ER---KR---ACP---TE single polypeptide chain - bilobed dimer |
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What kind of structure is the FA synthase composed of in fungus? |
two separate chains - double ring |
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What protein has a flexible phosphopantetheine arm? |
ACP |
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What is the only FA that FA synthase produces? |
palmitate (16:0) |
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What produces FAs that are longer than palmitate (16:0)? |
additional elongation cycles catalyzed by a separate set of enzymes called elongases |
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What is 18:0 |
stearate |
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What is 16:1(delta 9) |
palmitoleate |
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what is 18:1(delta 9) |
oleate |
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what is 18:2(delta 9,12) |
linoleate |
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In mammals, what introduces a cis double bond into fatty acyl-CoAs? |
fatty acyl-CoA desaturases |
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Where in the cell do fatty acyl-CoA desaturases introduce cis double bonds into fatty acyl-CoAs? |
in the smooth ER |
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At what carbon position do fatty acyl-CoA desaturases introduce cis double bonds into fatty acyl-CoAs? |
only at the 9th position |
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What do fatty acyl-CoA desaturases require for them to work? |
- O2 - cytochrome b5 which must be re-reduced using NADPH |
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What do we absolutely require linoleate (18:2Δ9,12) for? |
A precursor for other products such as prostaglandins |
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What promotes membrane fluidity in plants and bacteria? |
linoleate (18:2Δ9,12) |
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Linoleate (18:2Δ9,12) is an ________ _________ FA |
essential dietary |
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What is a major source of glycerol-3-PO4? |
dihydroxyacetone PO4 |
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What attaches PO4 groups to glycerol? |
glycerol kinase |
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What is the function of glycerol-3-phosphate dehydrogenase? |
removes the C=O bond on the second carbon of glycerol |
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Approx what % of FAs released by lipolysis are re-esterified to form TAGs? |
75% |
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List the three regulation methods and what they regulate with an example for each |
1. rapid - cellular regulation of enzymes (s to min) ex. high [ATP] inhibits phosphofructokinase-1 2. slow/moderate - hormonal regulation (min to h) ex. glucagon, insulin trigger signaling cascades 3. gradual adaptive - changes in gene expression (h to days) ex. high fat diet triggers β-oxidation enzyme synthesis |
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What is the committed step in the regulation of FA beta oxidation? |
the transfer of FAs into the mitochondria |
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What does a high concentration of [NADH]/[NAD+] inhibit in the mitochondria? |
β-hydroxyacyl-CoA dehydrogenase |
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What is thiolase in the mitochondria inhibited by? |
acetyl-CoA |
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what activates cutrate lyase? |
insulin |
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Acetyl-CoA carboxylase is regulated by what? |
metabolites (allosteric) and hormones (by phosphorylation) |
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What is the central enzyme that is regulated in FA biosynthesis? |
Acetyl-CoA carboxylase |
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What is the key target of regulation in FA synthesis? |
Acetyl-CoA carboxylase |
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What metabolite inhibits acetyl-CoA carboxylase? |
- palmitoyl-CoA |
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what metabolite activates acetyl-CoA carboxylase? |
citrate |
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What hormones cause phosphorylation of acetyl-CoA carboxylase ultimately inhibiting it? |
- epinephrine - glucagon |
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What promotes dephosphorylation of acetyl-CoA carboxylase activating it by polymerizing it into active acetyl-CoA filaments? |
insulin |
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True or False FA synthesis and degradation occur at the same time |
FALSE! FA synthesis and degradation are regulated so only one occurs at a time |
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malonyl-CoA inhibits which enzyme in FA beta oxidation? |
carnitine acyltransferase I |
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What is the major metabolic center of the human body? |
the liver |
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Where are nutrients first absorbed from? where is their first stop? What vein do they take to get there? |
- small intestine - the liver - the portal vein |
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Enzymes in the liver ________ ________ compounds ingested |
detoxify toxic |
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what role does the liver play when glucose levels are too high/low? |
high: - converts glucose to glycogen/FAs low: - release glucose by glycogen phosphorylation/gluconeogenesis - release ketone bodies as alternative fuel source |
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Why do hepatocytes change which enzymes they express? |
to optimally match the nutrients which make up the diet |
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What do adipocytes accumulate as in the cytoplasm? |
lipid droplets |
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What are the different metabolic pathways for glucose-6-PO4 in the liver? |
1. dephosphorylate into glucose for blood 2. store as liver glycogen 3. put through glycolysis ultimately producing acetyl-CoA whcih can be put through the TCA cycle 4. "..." acetyl-CoA can go on to be FA's stored as TAGs (releasing cholesterol on the way) 5. put through the pentose phosphate pathway making NADPH and ribose (nucleotides) |
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What is generally not used to make ketone bodies bc glucose is a better fuel? |
acetyl-CoA |
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List the different pathways FAs can take in the liver |
1. become liver lipids 2. go through beta oxidation producing acetyl-CoA 3. Acetyl-CoA can go into TCA cycle 4. electrons from TCA cycle can be used in oxidative phosphorylation 5. Acetyl-CoA can be used to produce ketone bodies 6. Acetyl-CoA can be used to make cholestrol which can be turned into bile salts/steroid hormones 7. FA's can become plasma lipoproteins 8. FA's can become FFA's in blood bound to albumin |
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what is the primary oxidative fuel in the liver? |
FAs |
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What can excess acetyl-CoA be used to make? |
- ketone bodies - cholesterol and other steroids |
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The liver can ______ TAGs from FA's |
synthesize |
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what is metabolic balancing coordinated by? |
hormones |
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What level should blood glucose be kept near in the blood? |
4.5 mM |
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What is the difference between a surface receptor and a nuclear receptor? |
Cell surface receptor - peptide/amine hormone binds to receptor on the outside of cell; acts through receptor w/o entering the cell - fast acting Nuclear receptor - steroid/thyroid hormone enters the cell; hormone-receptor complex acts in the nucleus - slower |
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True or false Peptide/amine hormones are generally faster acting than steroid hormones |
TRUE! |
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insulin stimulates which parts of the body to increase glucose uptake? |
- liver - adipose tissue - muscle |
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Which transporter facilitates glucose entry into the cell? |
GLUT4 |
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Where is glucose usage increased in the well-fed state? |
- glycogen synthesis - glycolysis - pyruvate entry into the TCA cycle - FA biosynthesis in the liver, and storage in adipocytes |
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Which pathway is acetyl-CoA carboxylase involved in? |
biosynthetic pathway |
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How do you know if blood sugar is high or low? |
different glucose transporters in blood - low affinity glucose transporters when high glucose in blood |
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Since the liver has the ability to make TAGs and glycogen it can be termed _________ |
lipogenic |
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What organs/tissues does epinephrine act on? |
- muscle - liver - adipose tissue |
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In the muscle what enzyme does epinephrine activate? |
phosphofructokinase-1 |
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In the active/early fasting state, what pathways are up/down regulated by glucagon in the liver? |
Up: - release of glucose-1P from glycogen - gluconeogenesis (to supply other tissues) - ketogenesis (ketone bodies for other tissues) Down: - glycolysis (liver burns FA instead of glucose |
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In the active/early fasting state, what pathways are up regulated by glucagon in adipose tissue? |
release of FAs |
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In a prolonged fast, what happens to glycogen stores in the liver? |
all stores exhausted |
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What provides the materials for gluconeogenesis in a prolonged fasting state? |
- AA from muscle tissue - glycerol from TAGs |
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what happens to the citric acid cycle when oxaloacetate is diverted into gluconeogenesis? |
TCA cycle shuts down |
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When is acetyl-CoA made into ketone bodies and why? What organs does ketone bodies supply fuel for? |
- in a prolonged fasting state - oxaloacetate is diverted into gluconeogenesis so citric acid cycle is shut down therefore acetyl-CoA cannot enter the cycle - brain and heart |
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what is released during a stressed state? |
cortisol |
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what kind of hormone is cortisol? |
a steroid hormone therefore slow acting |
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what slow acting hormone alters the kinds and levels of metabolic enzymes? |
cortisol |
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what kind of receptor does cortisol bind to? |
nuclear binding receptor |
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what organs does cortisol act on? |
- liver - adipose tissue |
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what disease is characterized by absence of/improper response to insulin? |
diabetes |
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what hormone is metabolism dictated by with a person who has diabetes? |
glucagon |
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what inhibits glycogen synthase kinase 3? |
its auto-inhibited by a substrate-like sequence at its N-terminus |
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What happens when glycogen synthase kinase 3 is phosphorylated by PKB? |
the autoinhibition sequence at its N-terminus binds to the catalytic site |
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Why can't the enzyme PKB further phosphorylate the substrate-like sequence on glycogen synthase kinase 3's N-terminus? |
The AA upstream is Pro not Ser/Thr` |
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List and explain the 4 functions of cellular membranes |
1. Compartmentalization of the organism into cells, and cells into organelles, allowing specialization of tasks 2. Permeability barrier that allows different molecular and ionic compositions inside and outside 3. Communication channel b/w inside and outside 4. Presentation of molecules that allow surface recognition (self/ not-self, tissue type etc) |
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what are cellular membranes defined by? |
their lipid organization |
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How are CHO present in the composition of cell membranes? |
present as modifications of both proteins and lipids |
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List the composition of a typical plasma membrane |
~45% lipid ~50% protein ~5% CHO |
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What is amphipathic? |
being both hydrophobic and hydrophilic |
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What molecule in the body is amphipathic? |
membrane lipids |
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What is glycerol used for? |
most lipids use it as their backbone |
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What do the different carbon positions usually have in glycerol? |
Position 1/2 are generally modified by FAs with an ester linkage Position 2 is generally occupied by an unsaturated FA Position 3 is occupied by a hydrophobic head group |
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Whats another name for phosphoglycerides? |
glycerophospholipids |
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Where is the phosphate group attached in phosphoglycerides? |
the third glycerol hydroxyl group |
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What may the head group of a phosphoglyceride be linked to the phosphate by? |
an alcohol group |
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What are some examples of phosphoglycerides? |
- phosphotidylcholine - phosphotidylethanolamine |
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What charge does the P group in phosphoglycerides give off? Whats the net result? |
- a negative charge - most membranes have an overall negative charge |
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What is the backbone in sphingolipids? |
sphingosine |
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What is sphingosine? |
a long chain amino alcohol |
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what kind of link connects FA to sphingosine? |
amide link |
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If only hydrogen is present at the head group of a sphingolipid, what is it called? |
ceramide |
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If the head group of a sphingolipid is phosphocholine, what is it called? |
sphingomyelin |
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What is the major nimal cell sterol? |
cholesterol |
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How many fused rings are in cholesterol? |
4 |
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The steroid nucleus of cholesterol has what kind of side chain? |
alkyl side chain |
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What is the polar head group of cholesterol composed of? |
alcohol (OH) |
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How long is extended sterol? |
about as long as palmitate (C16) |
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True or False There are no chemical variants of cholesterol |
TRUE! |
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Where are glycosphingolipids found? |
on the OUTER face of the plasma membrane |
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The __________ blood-type system _________ CHO structures presented by ____________ on your cell |
- ABO - reflects - glycosphingolipids |
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How can you tell what blood type you are? |
Look at sugars on outer surface of blood cells |
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What is the major lipid in plasma membrane? |
cholesterol |
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What is the major lipid in all membranes? |
phosphatidylcholine |
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when can monolayers of lipids form? |
at the air-water interface |
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How many acyl "tails" are in a FA that is forming a micelle? |
one |
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What shape are individual units that make up micelles? |
wedge-shaped |
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What shape are the individual units tha make up lipid bilayers? |
cylindrical |
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How thick is the central hydrophobic layer of lipid bilayers? |
3 nm |
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The lipid bilayer is ___________ to ions and polar molecules |
impermeable |
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What is in the centre of a liposome? |
aqueous solution |
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Artificial liposomes allow the study of what kind of transporters? |
membrane transporters |
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Vesicles __________ off from membranes are essentially _____________ |
- pinched - liposomes |
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What kind of things help get MOLECULES across the membrane? |
- transporters - channels |
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What proteins are required for signaling molecules for signaling molecules to be functional? |
receptors |
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What are proteins required for in the membrane? (doesnt involve signaling/transport) |
- build - maintain -reorganize the membrane |
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What proteins keep tissues together? |
adhesion proteins
- integrins - adherins |
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What are surface antigens required for on membranes? |
signal "self" to the immune system |
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How many AAs are there per turn of the alpha helix? |
3.6 |
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Are lipids free to move horizontally or vertically? |
horizontally |
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Where can amphitropic proteins be found? |
- in the cytosol - attached to the membrane ***some are covalently attached to a lipid anchor |
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List the 3 membrane proteins and how they associate with the membrane |
1. integral membrane protein associate tightly with the membrane, and generally at least have one domain that crosses the membrane (transmembrane domain) 2. Peripheral membrane proteins associate with the membrane (or other membrane proteins) through weaker interactions (ex. electrostatics) and can more readily be removed 3. Amphitropic proteins can be found in both the cytosol and attached to the membrane. Some are covalently attached to a lipid anchor |
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What is required in order to release a peripheral membrane protein? |
- pH change - chelator (removes stabilizing Ca2+)/chelating agent - urea - carbonate |
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What is required to remove a integral membrane protein? |
- detergent |
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What membrane protein requires phospholipase to be released? |
lipid-anchored membrane protein |
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What do peripheral membrane proteins interact with to stay attached to the membrane? |
ineract with the polar head groups of membrane lipids using electrostatic interactions and H bonds |
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Which membrane proteins use Ca to mediate interactions |
some peripheral membrane proteins |
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What membrane proteins can peripheral membrane proteins bind to? |
integral membrane proteins |
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What are the different lipid anchored membrane proteins and what are they attached to? |
- palmitoyl group on intergral Cys/Ser - N-myristoyl group on amino-terminal Gly - Farnesyl/geranylgeranyl group on carboxyl-terminal Cys - glycerophosphoinositol anchor on carboxyl terminus |
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What is glycophorin A? |
a single spanning transmembrane protein |
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List the properties of a membrane spanning protein |
- The membrane is crossed by asingle α-helix - The region contacting the fattyacid tails is made almostexclusively of hydrophobic aminoacids - The protein has an extracellulardomain (glycosylated) and anintracellular domain - These have more typical solubleamino acid compositions |
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How many "types" of integral membrane proteins are there? |
4 |
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What kind of plot predicts transmembrane helicies? |
- Hydropathy plot |
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What do hydropathy plots do? |
calculate the mean hydrophobicity of a protein segement |
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When is it likely that the membrane protein is a membrane spanning helix? |
If more than 20 residues in a row have a hgigh hydropathy index |
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Give an example of a multi-spanning transmembrane protein |
bacteriorhodopsin |
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How many transmembrane segments does bacteriorhodopsin contain? |
7 |
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What is the function of bacteriorhodopsin and what receptor family is it a part of? |
- uses light to pump protons across the membrane - member of the G-protein couple receptor family |
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What do the head group of annular lipids interact with? |
the more hydrophobic extracellular loops |
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What do the FA tails of annular lipids interact with? |
the hydrophobic regions of the transmembrane domain |
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What are 3 beta barrel integral membrane proteins? |
- FepA - OmpLA - Maltoporin |
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Bacterial and mitochondrial outer membrane proteins are generally built as __________ |
- Beta barrels |
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What is the minimum amount of residues whcih span the membrane for beta barrel intrgral membrane proteins? |
- 7 - dont show up on hydropathy plots |
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True or false You can predict whether a beta barrel is a transmembrane or cytosolic beta barrel |
FALSE! because of the nature of beta barrel you cant predict whether its a transmembrane or cytosolic beta barrel |
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What AA residues are concentrated where the polar head groups meet the acyl chains at the membrane interface? |
- tyrosine - tryptophan |
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Where are charged residues found at the membrane interface? |
- almost exclusively in the aqueous phase |
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What do glycoproteins contribute to? function as? |
- cell surface recognition - receptors for CHO recognizing proteins ex. lectins, viruses |
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What do O-linked CHO link to on glycoproteins? |
Ser/Thr side chain |
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What is generally the first sugar in O-linked CHO? |
N-acetylgalactosamine (GalNAc) |
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What is the first sugar in N-linked CHO? |
N-acetylglucosamine (GlcNAc) |
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What do N-linked CHO link to on glycoproteins? |
Asn side chains |
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What phase are lipids ordered in a paracrystalline state in the lipid bilayer? |
Gel phase (cold) |
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What state is the lipid bilayer in when there is no regular organization? |
liquid-disordered state (fluid state) |
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What kind of FAs favour a liquid-disordered state of the lipid bilayer? |
- unsaturated FAs - short chain FAs have a similar effect |
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What do cells regulate in order to achieve a constant membrane fluidity? |
lipid composition |
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True or False Cholesterol is relatively rigid |
TRUE! |
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Describe the effect of cholesterol on membrane dynamics with different lipid compositions |
Long, saturated FAs: cholesterol interferes with acyl chains interacting, increasing fluidity Unsaturated, cis FAs: cholesterol allows more efficient packing of kinked chains, decreasing fluidity |
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What are the three methods of diffusion in the membrane? |
1. uncatalyzed transbilayer ("flip-flop") diffusion 2. uncatalyzed lateral diffusion 3. catalyzed transbilayer translocation |
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What enzymes are used during catalyzed transbilayer translocations of lipids in the bilayer? |
- flippases - floppases - scramblases |
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What is the function of flippases and floppases? |
spend ATP to ensure that the inner and outer leaflets of the membrane have different lipid compositions |
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What is the function of scramblases? |
- randomise the lipids - ATP dependent |
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What is single particle tracking? |
following a single lipid molecule on a short time scale (μsec) |
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What may lipid and protein motion be restricted by? |
spectrin |
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What is spectrin apart of in the cell? hint: things move along this |
cytoskeleton |
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What does spectrin link to membrane proteins through? |
ankyrin |
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What are lipid rafts enriched in? |
- sphingolipids - cholesterol |
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What is the membrane like in membrane regions where there are lipid rafts? |
- thicker - less liquid |
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What proteins on the inside and outside of the cell associate with lipid rafts? |
inside: acylated proteins outside: GPI-linked proteins |
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Lists the reasons for intracellular trafficking |
- reorganization of membrane bound compartments (ex organelles) - movement of membrane components and soluble "cargo" between compartments - internalization/recycling/degradation of material from plasma membrane |
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List the process of intracellular trafficking |
1. budding (fission) of the vesicle from the parent membrane 2. transport of the vesicle 3. Tethering/docking at target membrane (recognition) 4. Fusion of vesicle and target membranes |
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During what key processes do SNAREs mediate membrane fusion? |
- insulin secretion - up-regulation of glucose transporters - transport between ER and Golgi - phagocytosis - neurotransmitter release |
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Which SNAREs are single-spanning transmembrane proteins? |
v-SNARE t-SNARE |
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What is the purpose of SNAP25? |
SNAREs (v- and t-) have an extended helical domains which can interact to form a coiled-coil structure with SNAP25 |
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Which original characteristic of the fluid mosiac model of biological membranes need updating? |
lipids and proteins flow freely in a sea of lipids |
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What are lipid membranes impermeable to? |
-ions - polar molecules |
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What molecules can cross the lipid membrane slowly? |
small uncharged molecules ex. ethanol, glycerol |
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What molecules cross the lipid membrane quickly? |
- hydrophobic molecules ex. steroid hormones - gasses ex. O2, CO2, N2, CO, NO |
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Where are ion concentration gradients found? |
- across the plasma membrane - across organelle membranes |
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List and explain the different membrane transports (6) |
1. simple diffusion - nonpolar compounds only, down concentration gradient
2. facilitated diffusion - down electrochemical gradient 3. Ionophore-mediated ion transport - down electrochemical gradient 4. Ion channel - down electrochemical gradient, may be gated by a ligand or ion 5. primary active transport - against electrochemical gradient driven by ATP 6. secondary active transport - against electrochemical gradient, driven by ion moving down its gradient |
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When is ΔG negative? |
if c1>c2 |
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What form of heat is produced when c1 moves to c2 down its concentration gradient? |
exergonic (gives off energy) therefore spontaneous |
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To cross the lipid bilayer, _________ must be removed from their __________ shell |
- solutes - hydration |
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How do transporters and channels work in regards to the energy barrier? |
They lower the energy required to break the interactions present between solutes and water molecules to cross the membrane |
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How do transporters compensate for the lost solvation energy? |
by making strong interactions with the solute |
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Rate of membrane channel transport is __________ to substrate concentration and is not __________. |
- proportional - saturable |
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How much water goes through kidney aquaporins everyday? |
170L |
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What gradient do aquaporins follow? |
osmotic gradient |
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How wide are aquaporins? |
2.8 Å (just wide enough for one H2O) |
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What ensures protons (in the form of H3O+) cannot pass through aquaporins? |
elctrostatic repulsion by arginine residues |
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Aquaporins are _______ by a variety of _________- |
- gated - mechanisms |
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What can aquaporin variants transport? |
- glycerol - urea |
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What AA is strategically placed in aquaporin to orient water through in the right way? |
His180 |
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what charge does the top of the aquaporin have and why? |
negative charge to repel ion and other negative molecules |
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What does Arg do inside the aquaporin? |
acts as a gatekeeper, has a positive charge so doesnt let positive things go through and repes them. Also contributes to shape of aquaporin |
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List and describe the 3 classifications for membrane transport |
1. uniports - transport a single solute 2. symports - co-transport two different solutes in the same direction 3. antiports - transport two different solutes in opposite directions |
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Transporters are __________ selective and ___________. |
- highly - stereospecific |
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The rate of transport is ____________, so ____________ substrate concentration beyond a certain level _______ _______ further increase their rate (similar to an enzyme). |
- saturable - increasing - does not |
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Lists the steps involved in passive transport of glucose by GLUT1 |
- transporter is open to the outside of the membrane - glucose binding pocket in middle of membrane is empty - D-glucose binds from the extracellular side of the membrane - transporter switches its conformation - glucose binding site is then open to the cytoplasmic side of the membrane where glucose is released - empty transporter switches back to starting conformation - net result is one glucose molecule transported down its concentration gradient |
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what are active transporters often called? |
pumps |
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Many active transporters are powered by....? |
ATP hydrolysis |
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Whats another name for active transporters? |
ion-pumping ATPases |
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what generates ion gradients across membranes? |
active transporters |
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Whats the concentration of Na outside/inside the cell? |
outside: ~150 mM inside: ~10 mM |
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Whats the concentration of Cl outside/inside the cell? |
outside: ~110 mM inside: ~5 mM |
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Whats the concentration of K outside/inside the cell? |
outside: ~5 mM inside: ~140 mM |
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Whats the concentration of Ca2+ outside/inside the cell? |
outside: ~5 mM inside: ~1 mM |
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Ion gradients represent an ___________ potential. |
- electrochemical |
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How many Na/K ions move in/out when worked on by Na K ATPase? |
in: 2 K+ ions out: 3 Na+ ions |
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Which ATPase uses 1/4 of your ATP when at rest? |
Na K ATPase |
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The Na K ATPase is a _____-type ATPase |
P |
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The Na K ATPase is organized as an ________ tetramer |
(α2β2) |
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which subunit in the Na K ATPase performs transport? |
α subunit |
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What kind of transporter is Na K ATPase? (uniport, symport or antiport) |
antiport |
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What is the net transport of Na K ATPase? |
one positive charge out of the cell |
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What does Na K ATPase set up across the cellular membrane? |
electrical potential |
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What are three things the Na K ATPase does besides move ions in and out? |
- controls cell volume (via osmotic strength) - drives active transport of other species - renders nerve cells electrically excitable |
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Explain the transport cycle of Na K ATPase (8 steps) |
- cycle starts with transporter dephosphorylated with its binding site facing inside the cell - 3 Na+ ions bind from inside the cell - transporter is phosphorylated on the cytosolic side at the expense of one ATP - phosphorylation induces a conformational change, opening the binding site to the extracellular face - 3 Na+ ions are released and 2 K+ ions bind - the transporter is dephosphorylated - transporter again changes conformation so the binding site faces the inside of the cell - 2 K+ ions are released |
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What relation do F-type ATPases have to P-type ATPases? |
unrelated |
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Are F-type ATP-driven proton transporters reversible? |
yes! |
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F-type ATPases are composed of two subunits: Fo and F1. Fo is not a zero, what does it stand for? |
orythromsins which inhibits this F-type ATPase |
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How many Na+ ions enter the cell with every glucose molecule? |
2 |
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List and describe the 3 differences b/w channels and transporters |
1. rate of flux - channels are much faster 2. saturability - channels dont saturate 3. Gating - channels are often gated |
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Give 3 distinguishing characteristics of an ion channel |
1. present in plasma membranes of all cells 2. together with ion pumps, they define the permeability of membranes to ions 3. move ions very fast across membrane |
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Describe the basic organization of the K+ channel |
- built as a tetramer of 4 identical SU - each SU has two transmembrane α-helices - the inner helix lines the channel at the center of the complex - the outer helix (N-terminal) interacts with the bilayer - a third shorter pore helix contributes to specificity - the overall complex has a cone shape |
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K+ ions in solution are ______, increasing their effective __________. |
- solvated - diameter |
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What is perfectly spaced in K+ channels to optimally interact with K+? |
carbonyl oxygen |
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What helps stabilize the positive charge in K+ channels? |
the helix dipole of the third helix |
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How much more selective is the K+channel for K+ tha Na+? |
10,000 fold |
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How many carbonyl atoms coordinate one un-hydrated K+? |
8 |
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what in the K+ channel specify positively charged ions? |
- partial negative charges on C=O - dipole of third helix |
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Why is Na unlikely to go through a K channel? |
- channel size is optimal for K and Na is smaller so wont get the same energy of interaction - Na is more condensed and has a higher energy of solvation meaning it takes more energy to strip water off |
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What does it mean when a channel is gated? |
1. by default they are closed, let nothing past 2. they open in response to a specific stimulus 3. an inbuilt timer closes them again after a short delay, even if the stimulus is still present |
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What are the two different gated channels? |
- ligand-gated - voltage-gated |
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What is the most obvious difference b/w the Na channel and K channel? |
Na has a narrower specificity pore b/c Na is smaller |
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which helix is the pore forming helix of Na channel? |
α-helix 6 |
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Which helix in the Na channel can move in response to changing membrane voltage? |
voltage sensing helix 4 |
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Which helix in the Na channel is also called the activation gate? |
pore lining helix 6 |
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What is the inactivation gate in the Na channel? |
- a small soluble domain inserted into the loop connecting domains 3 and 4 - length of tether dictates how long it takes to inactivate channel |
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Explain the steps involved in opening the volatge gated Na+ channel |
1. Helix 4 has a high net positive charge and is sensitive to membrane voltage
2. the net negative charge inside the cell pulls it inward 3. When membrane is depolarized helix 4 relaxes and moves towards outside 4. coupled movements in helix 6 (lining the pore) opens the channel 5. after opening the channel is quickly blocked by the inactivation loop, stopping ions from passing |
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what toxin binds to Na channels of neurons? |
tetrodotoxin from puffer fish |
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Describe signaling generally (4 steps) |
1. The presence of certain stimuli (generally molecules) in their environment elicits specific responses from receptive cells 2. The presence of these molecules effectively represents information 3. These molecules act as signals that are detected by specific receptors 4. Signals are converted to a cellular response which always involves a chemical process |
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What is signal transduction? |
conversion of the initial stimulus (primary messenger) into a chemical change and then propagation of that change in different forms in the cell |
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What are the properties of signal transduction? (5) |
1. Very specific 2. Amplify the initial signal 3. Signaling is mediated by modular components with (partly) interchangeable parts 4. Show desensitization and adaption to a persistent signal 5. Have mechanisms to integrate conflicting signals |
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What are the 3 factors that account for extraordinary sensitivity of signal transducers? |
1. Receptors have very high affinity for their ligands therefore very low [ligand] can activate 2. Cooperativity in the ligand-receptor interaction results in large changes in activity upon ligand binding 3. once activated, enzyme cascades amplify the signal |
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What are the 6 types of signal transducers? Describe how they work. |
1. G protein-coupled receptor - External ligand binds to receptor to activate an intracellular GTP-binding protein which regulates an enzyme that generates an intracellular second messenger 2. Receptor tyrosine kinase - ligand binding activates tyrosine kinase activity by autophosphorylation 3. Gated ion channel - Opens or closes in repsonse to concentration of signal ligand or membrane potential 4. Nuclear response - Hormone binding allows the receptor to regulate the expression of specific genes 5. Receptor guanylyl - ligand binding to extracellular domain stimulates formation of second messenger cyclic GMP 6. Adhesion receptor (integrin) - Binds molecules in extracellular matrix, changes conformation, thus altering its interaction with cytoskeleton |
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What is required for transmission of a nerve impulse? (2) |
- action potential carries electrical signal down axon - neurotransmitter carries signal to next cell |
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Describe what happens with the action potential in regards to Na and K channels and the charges in the cell. (6) |
1. In response to local membrane depolarization, voltagegated Na+ channels open 2. Na+ flows in (down gradient), resulting indepolarizationΔΨ = +30 mV 3. Na+ channels quickly inactivate themselves 4. Voltage-gated K+ channels open in response todepolarization 5. K+ flows out (down its gradient)ΔΨ = -75 mV and you get hyperpolarization of the membrane 6. K+ channels inactivatedΔΨ = -60 mV and you get polarization |
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What triggers the release of a neurotransmitter when the electrochemical wave reaches the neural synapse? |
Ca2+ influx |
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What relays the electrical signal from a motorneuron to the muscle fiber at a neuromuscular junction? |
Acetylcholine |
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What receptor binds acetylcholine? |
nicotinic acetylcholine receptor |
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Nicotinic acetylcholine receptor has how many SUs with how many helicies in each? |
- 5 SU, 4 distinct types of SU, two copies of alpha - 4 helicies in each |
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What helicies surround the channel in a AchR? |
M2 ampipathic helicies |
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AchR activates by doing what? |
rotating its SUs |
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How many transmembrane helicies does each SU of AchR have? |
4 |
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How many binding sites are in an AchR? |
2 |
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What blocks the channel of AchR when binding sites are emtpy? |
Leu residues |
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Signals from which molecules are transduced by G protein-coupled receptors? |
- glucagon - epinephrine |
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List the 3 components of heterotrimeric G protein-coupled receptor signaling. Include second messengers. |
1. Plasma membrane receptor with 7 transmembrane helices e.g. epinephrine receptor 2. heterotrimeric guanosine nucleotide-binding protein (G protein) 3. Intracellular enzyme that generates a 2nd messenger Second messenegers: - cAMP - cGMP - inositol 1,4,5-triphosphate (PIP3) |
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Describe how heterotrimeric G-proteins are turned on/off and what they are composed of. |
- comprised of 3 separate SUs: α, β and γ - When Gα has GDP bound, the complex is inactive - Binding a GPCR-ligand complex opens up the Gαsubunit, allowing GTP to bind instead of GDP - Gα then dissociates from the Gβ/Gγ complex making the Gα-GTP complex active & signaling - Gα has an intrinsic GTPase activity that cleaves GTP - Once GTP is cleaved, the Gα-GDP complexreassociates with Gβ/Gγ - Restoring the G protein to its inactive state |
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List the steps involved in the activation cycle of G-protein |
1. Gs which has GDP bound is turned off; it cannot activate adenylyl cyclase 2. Contact of Gs with receptor which has hormone bound to it causes displacement of GDP and GTP binds instead 3. Gs with GTP bound dissociates into alpha SU leaving beta and gamma behind. 4. Gsalpha-GTP is turned on and can activate adenylyl cyclase 5. GTP bound to Gsalpha is hydrolysed by the proteins intrinsic GTPase which turns itself off. 6. The inactive alpha SU then reassociates with the beta/gamma SU |
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Give the steps involved in epinephrine (β-Adrenergic) signal transduction pathway |
1. epinephrine binds to its specific receptor 2. Horomone-receptor complex causes the GDP bound to Gsalpha to be replaced by GTP, activating Gsalpha 3. Activated Gsalpha separates from Gsbeta/gamma going to adenylyl cyclase and activating it. **many Gsalpha SU may be acitvated by one occupied receptor 4. Adenylyl cyclase catalyzes the formation of cAMP 5. cAMP activates PKA 6. Phosphorylation of cellular proteins by PKA causes the cellular response to epinephrine 7. cAMP is degraded, reversing the activation of PKA |
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What tethers PKA to the region of the cell where adenylate cyclase and its targets are localized? |
A-kinase anchoring protein (AKAP) |
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How is PKA inhibited? |
By binding of the regulatory domain to the substrate binding cleft of PKA |
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How is PKA activated? |
- 2 cAMP molecules bind to each regulatory SU - Forces a conformational change in the reg SU - The catalytic SU is released and can phosphorylate substrates - only works in region close to where AKAP is |
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List what happens in response to epinephrine resets |
- Gα subunit slowly hydrolyses GTP, returning theprotein to an inactive state - GTPase activator proteins (GAPS) greatlystimulate the GTPase activity of Gα - Cyclic nucleotide phosphodiesteraseshydrolyses cAMP to AMP - This allows the regulatory domain to recaptureand inactivate the PKA kinase domain - β-adrenergic receptor is phosphorylated andinternalized, where it can no longer transmit theepinephrine signal |
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List the steps involved when the epinephrine receptor is internalized |
1. binding of epinephrine to beta adrenergic receptor triggers dissociation of Gsbeta/gamma from Gsalpha 2. Gsbeta/gamma recruits betaARK tot he membrane where it phosphorylates Ser residues at the carboxyl terminus of the receptor 3. Beta-Arrestin binds to the phosphorylated carboxyl-terminal domain of the receptor 4. Receptor-arrestin complex enters the cell by endocytosis 5. In endocytic vesicle, arrestin dissociates; receptor is dephosphorylated and returned to cell surface |
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describe what happens when insulin binds to its receptor |
- insulin binding activates the tyrosine kinase activity of the intracellular domain - the tyrosine kinase domains autophosphorylate making them active on other targets |
