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BIOC 3560 > fatty acid metabolism > Flashcards

fatty acid metabolism Flashcards

1
Q

naming fatty acids

A
  • Greek letters - α,β…ω used mostly for talking about sites of chemical reactivity
  • Numbering carbons-
    C1, C2 … Cn used for locations of features, e.g. double bonds
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2
Q

what is the main storage of energy

A
  • in form of lipids
  • mipid catabolism mobilizes the organisms main energy

Circulating fuels 400kJ (includes glucose, fatty acids, etc)

glycogen: 4000KJ
aminoacids: 100,000 KJ

triacylglycerols 600,000 KJ

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3
Q

what are triacylglycerol

A

Mixed triacyglycerol - main storage form

Abbreviated as TAG

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4
Q

how are FA stored, what are they coated in, where does degredation occur?

A

Fatty acids are stored as triacylglycerol in “fat cells” i.e. adipocytes

TAG in adipocyctes coated by the protein perilipin to form lipid globules

Fatty acid degradation occurs in the mitochondria of cells (e.g. muscle)

Need to get TAG reserves to target tissue

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5
Q

explain the preparation of the mobilization of FA from adipocytes (1-4)

A

1) Hormone (glucagon) binds receptor
2) activated glucagon receptor sends signal (via G protein), kinase is activated

*cAMP comes along activating kinase

3) PKA phosphorylates a lipase, HSL (hormone sensitive lipase), sticks it into membrane of lipid droplet

*PKA has a second target

4) PKA phosphorylates perilipin (transmembrane protein)
- phosphoylated perilipin releases CGI

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6
Q

exaplin the release of FA in the Mobilization of Fatty Acids from adipocytes (5-8)

A

5) Phosphorylated perilipin releases the protein CGI
6) CGI activates Adipocyte triacyl glycerol lipase (ATGL), which releases first FA
7) HSL release second FA from diacylglycerol
8) Monoacyl glycerol lipase (MGL) cleaves the third FA from monoacyl glycerol

*monoacyl glycerol is not regulated

  • fatty acisd diffuse out the lipid droplet
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7
Q

explain FA transport in the Mobilization of Fatty Acids from adipocytes (9-11)

A

9) Released fatty acids enter the bloodstream, where they bind to serum albumin
10) FA transporter in the muscle cell takes up fatty acid
11) FA will then be oxidized in the muscle cell via β- oxidation

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8
Q

explain fatty acid oxidation: where does it start, where does it occur and how does it get there

A
  • process starts in cytoplasm, but occurs mostly in mitochondria
  • transport of Fatty Acids into the Mitochondria: if 12 C or less no need for transporter, if larger than 14 C fatty acids must go through carnitine shuttle
  • Cytoplasmic fatty acids are first converted to fatty acyl-CoA (by acyl CoA synthetase)
  • Fatty acyl group is then transferred to carnitine (by carnitine acyltransferase I)
  • Fatty acyl-carnitine enters mitochondria (via acyl-carnitine/carnitine transporter)
  • Fatty acyl-CoA regenerated within the mitochondrion (by carnitine acyltransferase II)

*in order for carnitine transporter to work need to change nature of fatty acid)

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9
Q

how does the carnitine shutle transport FAs into mitochondiria

A
  • Fatty acyl-carnitine formed at outer membrane or intermembrane space of mitochondria

-It moves into matrix by facilitated diffusion
-Acyl group transfered to mitochondrial CoA by carnitine acyltransferase II
-Acyltransferase I is inhibited by malonyl CoA
(Inhibition prevents simultaneous synthesis and degradation of fatty acids, malonyl CoA is involved in synthesis of fatty acids, so we are importing fatty acids in and dont want both pathways at once)

*there is a transporter at inner mitochondrial membrane

*acyl transferase II recycles it back from carnitine fatty acid molecule

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10
Q

explain the complete oxidation of fatty acids

A

*whole process occurs in mirochondria

  • three stages
    (1) β-oxidation produces acetyl CoA

*long chain fatty acid is oxidized to yeild acetyl CoA (cuts at every 2 carbon)

(2) acetyl CoA is oxidized in the citric acid cycle

*Acetyl groups are oxidized to CO2 via the citric acid cycle

(3) NADH and FADH2 donate e- to mitochondrial respiratory chain, ultimately yielding ATP

*electrons from stages 1 and 2 pass to O2 to make ATP

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11
Q

how does β-oxidation converts fatty acids to acetyl-CoA

(what end is acetyl CoA removed from)

A
  • One cycle of β- oxidation results in one acetyl-CoA being removed from the carboxyl end of the fatty acid chain
  • In each pass two carbon atoms are removed
  • Continues until only acetyl-CoA is left
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12
Q

Explain steps 1 and 2 of FA degredation

A

1) Dehydrogenation

- exposre to acyl-CoA dehydrogenase, strip a hydrogen atom off

fatty acyl-CoA (Cn) -> FADH2 + trans-Δ2-enoyl-CoA

2) Hydration

Use enoyl-CoA hydratase (uses water)

trans-Δ2-enoyl-CoA -> L-β-hydroxyacyl-CoA by

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13
Q

explain step 3 and 4 of FA degradation

A

3) Dehydrogenation

  • uses β-hydroxyacyl-CoA dehydrogenase

L-β-hydroxyacyl-CoA -> NADH + β-ketoacyl-CoA

4) Cleavage

  • uses acyl-CoA acetyltransferase (thiolase)

β-ketoacyl-CoA -> acetyl CoA + fatty acyl-CoA (Cn-2)

*each loop involves the 4 steps to generate 1 mol of acetyl CoA

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14
Q
A
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15
Q

what tpes of problems occur in oxidation of faty acids

A

Problem 1: Cis bond

  • β-oxidation works on trans double bonds

Problem 2: Two double bonds

  • Similar to cis bond problem

Problem 3: Odd number carbons

  • β-oxidation works on even number of carbons
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16
Q

how is an odd number of carbon atoms overcome

A
  • Initially β-oxidation proceeds normally
  • Propionyl-CoA (3 C atoms) cannot be oxidized by acyl-CoA dehydrogenase
  • Instead a separate three enzyme pathway carboxylates propionyl-CoA to succinyl-CoA (4 C atoms)
  • Succinyl-CoA is part of TCA

*bascially just add a carbon to make it an even number

*know it carboxylates

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17
Q

How do you get over a cis double bond

A
  • β-oxidation enzymesi gnore the kink and process cis-fatty acids normally
  • β-oxidation proceeds as normal for three rounds,
  • cis-Δ3 FAs are not substrates for acyl-CoA dehydrogenase because C3 is already in a double bond
  • The enzyme Δ3,Δ2-enoyl-CoA isomerase can move the double bond
  • It converts the cis-Δ3 FA to trans-Δ2
  • trans-Δ2 FA is a substrate for enoyl-CoA hydratase
  • β-oxidation proceeds normally

**Net result: one fewer FADH2 (because acyl-CoA dehydrogenase skipped this cycle)

*understand that we just rearrage using enzymes like isomerases to relocate double bonds so they can act as substrates for beta oxidation

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18
Q

how do you fix two double bonds (first steps)

A
  • first double bond is in the 9 position (odd), the second will be at the 12 position (even)
  • β-oxidation will sequentially produce both cis-Δ3 and cis-Δ4 FA intermediates
  • rxn proceeds as with one double bond to produce a cis-Δ3,Δ6 FA
  • cis-Δ3,Δ6 FA is converted to trans-Δ2 cis-Δ6 FA by Δ3,Δ2 enoyl- CoA isomerase (just relocates it)
  • trans-Δ2 cis-Δ6 FA is substrate for the hydratase
  • This β-oxidation cycle thencompletes normally, yielding a cisΔ4 FA
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19
Q

how to you solve two double bonds (second half of steps)

A
  • cis-Δ4 FA substrate, acyl-CoA dehydrogenase produces a trans-Δ2 cis-Δ4 FA
  • The resulting conjugated double bond cannot be hydrated by enoyl-CoA hydratase
  • Reduced by 2,4-dienoyl-CoA reductase, yielding a trans-Δ3 FA
  • trans-Δ3 FA is then converted to trans-Δ2 FA by Δ3,Δ2 enoyl- CoA isomerase

β-oxidation then proceeds normally

*dont need to memorize names of all intermediates and enzymes for the problems

*understand that we just rearrage using enzymes like isomerases to relocate double bonds so they can act as substrates for beta oxidation

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20
Q

what are ketone bodies?

A
  • Acetyl-CoA can enter the TCA

*mobilizing fat stores

  • Optionally, acetyl-CoA in the liver can be turned into ketone bodies
  • Ketone bodies allow acetyl- CoA to enter the citric acid cycle in a different cell
  • This frees up CoA, so further FA can be degraded
  • Ketone bodies act as an alternative fuel e.g. for brain (which cannot use FAs)

*by generating ketone bodies we are sending acetyl CoA and package them as ketone bodies which freeze up CoA so further fatty acids can be degraded (act as alternative fuel source)

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21
Q

explain ketone body anabolism

A

Acetoacetate is formed by condensing three acetyl-CoA molecules, then cleaving one

D-β-hydroxybutyrate is formed by reducing acetoacetate

Acetone is a minor product, formed by decarboxylation, and is exhaled

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22
Q

Explain ketone body catabolism

A

Conversion back to acetyl-CoA

In the end, two molecules of acetyl-CoA are regenerated for the citric acid cycle

  • product is 2 acetyl CoA
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23
Q

What is fatty acid biosynthesis

A

Occurs in the cytoplasm

Is reductive, using NADPH

Acetyl-CoA is the starting substrate, and is converted to malonyl-CoA as the committed step

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24
Q

what is the acetyl gorup shuttle

A
  • Acetyl-CoA is not directly transported from the mitochondria to the cytosol
  • mitochondrial acetyl-CoA is combined with oxaloacetate to produce citrate
  • Citrate is transported to the cytosol
  • Citrate lyase in the cytosol produces acetyl-CoA

Oxaloacetate is reduced to malate, which can then return to the mitochondria either directly, or after decarboxylation to pyruvate

  • Mitochondrial enzymes use malate/pyruvate to regenerate oxaloacetate
  • Most of these enzymes are part of other metabolic pathways – e.g. TCA, gluconeogenesis
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25
Q

explain fatty acid biosynthesis using malonyl CoA (how is malonyl CoA formed)

A
  • Fatty acids are made from the activated intermediate malonyl-CoA (not found in FA degradation)
  • Malonyl-CoA is made from acetyl CoA and HCO3 in an ATP dependent reaction
  • This is reaction catalysed by acetyl-CoA carboxylase
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26
Q

What is acetyl CaA carboxylase

A
  • Biotin carrier protein
  • carries the biotin cofactor
  • Biotin carboxylase
  • enzyme that uses ATP to activate biotin with CO2
  • Transcarboxylase
  • transfers CO2 from biotin to acetyl CoA to form malonyl-CoA
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27
Q

What is the fatty acid biosynthesis cycle

A

Carbon atoms are added two at a time by a repeating, four step sequence

  1. Condensation of malonyl-CoA with growing FA
  2. Keto reduction
  3. Dehydration
  4. Enoyl reduction
  • Saturated acyl groups are the substrates for condensation with activated malonyl groups
  • Each cycle extends the chain by 2 carbon atoms
  • Reduction is accomplished using NADPH The growing fatty acid chain is covalently attached to a small protein – Acyl carrier protein (ACP)
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28
Q

explain step 0-1 in the fatty acid biosynthesis cycle

A

Step 0

  • Fa synthase gets charged with acetyl-CoA and malonyl-CoA
  • Malonyl/acetyl-CoA-ACP transferase

Step 1

  • Condensation of activated acyl group with malonyl CoA by β-ketoacyl-ACP synthase

** the CO2 that acetyl-CoA carboxylase added is lost during condensation

29
Q

explain step 2 in the fatty acid biosynthesis cycle

A

reduction of β-keto to β-alcohol by β-ketoacyl-ACP reductase

30
Q

explain step 3 in fatty acid biosynthesis

A

Elimination of H2O to form C=C by β-hydroxyacyl-ACP dehydratase

31
Q

explain fatty acid synthase organization

A

Plants and bacteria: separate polypeptides

Vertebrates: single polypeptide, bilobed dimer

Fungi: Two separate chains (double ring)

32
Q

explain mammalian fatty acid synthase

A
  • All reactions are catalyzed by a single multi-enzyme complex: fatty acid synthase (FAS)
  • 6 enzyme functions plus ACP in one polypeptide chain
33
Q

how is fatty acid synthesis initiated

A
  • Malonyl/acetyl-CoA ACP transferase (MAT) transfers acetyl from Acetyl-CoA to Acyl Carrier Protein (ACP)
  • β-ketoacyl synthase (KS) transfers acetyl from ACP to itself
  • MAT then transfers malonyl group to ACP
  • KS is now ready for the first condensation step
34
Q

what are the steps in FA synthesis

A
  1. condensation (KS)
  2. Reduction of B-keto group (KR)
  3. Dehydration of (DH)
  4. Reduction of double bond (ER)
  5. Translocation of butyryl group to Cys on B-ketoacyl-ACP sythase (KS)
  6. Recharging of ACP with another malonyl group (MAT)
35
Q

What is the first step of FA synthesis

A
  • condentsation

fatty acid synthase complex charged with an acetyl and malonyl group

-CO2 removed

36
Q

What is step 2 of FA synthesis

A

B-Keto reduction

  • have b-ketobutyryl-ACP, use NADPH + H+ –>NADP+ to get b-hydroxybutyryl-ACP
37
Q

What is step 3 of FA synthesis

A

dehydration

  • B-hydroxybutyryl-ACP -> trans-Δ 2 Butenoyl ACP
38
Q

What is step 4 of FA synthesis

A

enoyl reduction (reduction of double bond (ER)

  • uses NADPH + H+ –> NADP+
  • butyryl ACP –> trans-Δ 2 Butenoyl ACP
39
Q

What is step 5 of FA synthesis

A
  • translocation
  • translocation of butyryl group to Cys on B ketoacyl-ACP synthase (KS)
40
Q

what occurs at the beginning of second round of FA synthesis

A
  • KS transfers butyryl group from ACP to itself
  • MAT transfers new malonyl group to ACP
  • KS condenses malonyl group with butyryl group
41
Q

explain the synthesis of palmitate

A
  • First acetyl group ends up furthest from the carboxylate
  • Substrate is physically linked to FAS through the whole process
  • Palmitic acid (C16 FA) is released from FAS by cleavage by the last enzyme, thioesterase
  • somethines we need unsaturated FA or longer chain FA
42
Q

what is the difference between fatty acid oxidation and fatty acid biosynthesis

A
43
Q

explain the sysnthesis of longer chain fatty aicds

A
  • Palmitate is the precursor for longer- chain fatty acids (bc end result of other proces)
  • Elongation occurs 2 carbons at a time (still using malonyl)
  • CoA instead of ACP
  • Different enzymes for different steps (generic names are elongases and desaturases)
  • plants can deaturated furer making linoleats 18:2 but humans cannot

*no longer on fattyacid synthase

44
Q

explain the Production of Δ9 unsaturated fatty acids

A

In mammals, fatty acyl-CoA desaturases make cis double bonds

They desaturate only at the 9 position, so palmitate (16:0) is oxidized to palmitoleate (16:1Δ9), and stearate (18:0) to oleate (18:1Δ9)

Fatty acyl-CoA desaturases require oxygen and cytochrome b5, which must be re-reduced using NADPH

*cyt b5 is an iron dep protein but is not a heme

45
Q

where do we get other unsaturated fatty acids

A
  • Mammals cannot further desaturate Δ9 FAs

However, we absolutely require linoleate (18:2Δ9,12) as a precursor for other products such as prostaglandins

Plants and bacteria make linoleate to promote membrane fluidity

Linoleate is therefore an essential dietary fatty acid

46
Q

how are triacylglycerols assembled

A

Fatty acids are stored as triacylglycerols

Two sources of glycerol-3-PO4 (comes from the glycolysis pathway, glucose is brocken down)

Major source is dihydroxyacetone PO4

Acyl-CoA synthetases activate FA groups with CoA

Acyl transferases then transfer the FA to glycerol-3-PO4

47
Q

explain the triacylglycerol cycle

A

Triacylglycerol can be made in adipose tissue or liver

It is simultaneously broken down (only in adipose tissue)

Approximately 75 % of fatty acids released by lipolysis are re- esterified to form triacylglycerols

This futile cycle may help make the system more responsive to quickly changing needs

48
Q

What are the levels of control for regulation methods

A

i. Rapid - cellular regulation of enzymes (s to min)
* ex: high [ATP] inhibits phosphofructokinase-1
ii) Slow/moderate – hormonal regulation (min to h)
* ex: glucagon, insulin trigger signaling cascades
iii) Gradual/adaptive – changes in gene expression (h to days)
* ex high fat diet triggers β-oxidation enzyme synthesis

49
Q

explain regualtion of fatty acid β-oxidation

A
  • The transfer of fatty acids into the mitochondria = committed step

*once in the mitochondria, fatty acids will be broken down by β- oxidation

  • The most important regulatory mechanism is malonyl- CoA inhibition of carnitine acyltransferase I
  • In the mitochondria:

* high [NADH]/[NAD+] inhibits β-hydroxyacyl-CoA dehydrogenase

*acetyl-CoA inhibits acyl-CoA acetyltransferase (thiolase)

50
Q

explain Regulation of Fatty Acid Biosynthesis

A

Citrate lyase is activated by insulin

Acetyl-CoA carboxylase catalyzes the committed step

*Regulated by both metabolites (allosteric) and hormones (by phosphorylation)

51
Q

explain the regulation of acetyl-CoA carboxylase

A
  • Acetyl-CoA carboxylase (ACC) is the key target of regulation in FA synthesis
  • Regulated by metabolites :
  • palmitoyl-CoA (ultimate product) inhibits ACC
  • citrate (acetyl-CoA precursor) activates ACC

Regulated by hormones:

  • Epinephrine/glucagoncausesphosphorylation of ACC, inhibiting it
  • Insulin promotes dephosphorylation of ACC, activating it by polymerizing it into active ACC filaments (left)
52
Q

explain reciproval regualtion of fatty metabolism

A

Fatty acid synthesis and degradation are regulated so only one occurs at a time

  • have ACC enzyme (acetyl CoA carboxylase, its incative then phosphorylated, ACTIVE IN DEPHOS STATE)
  • either fatty acids synthesis or fatty acid B oxidation (in mitochondira)
  • high blood glucose inc insulin, have phosphatase that dephosphorylates ACC activating it.
  • not acetyl CoA -> Malonyl CoA (inhibits carnitine acyl transferase, alonyl CoA is precuser for FA so makes sense it is inhibiting thing to break it down)

*low blood glucose inc glucagon activating PKA which phosphorylates ACC (low blood glucose is trigger fatty acid oxidation)

53
Q

what is the role of the liver

A
  • major metabolic center of the human body acting as an overall metabolic (glucose) buffer:
  • Convertes glucose to glycogen or fatty acids when levels are too high
  • Releases glucose from glycogen or gluconeogenesis when levels are too low
  • Releases ketone bodies as an alternative fuel
  • Hepatocytes change which enzymes they express to optimally match the nutrients which make up the diet
54
Q

what is the role of adipose tissue

A

Conver tglucose to fatty acids

Store fatty acids as triacylglycerol, which accumulate as lipid droplets in the cytoplasm

They respond to hormonal signals such as epinephrine and insulin

– Storing TAGs when energy is abundant, and hydrolyzing them when energy is lower

The released fatty acids can then serve as a fuel for most tissues in the body

55
Q

explaint he metabolic pathway of glucose 6 PO4 in the liver

A

* goal is to get glucose into the blodo stream

*cetyl-CoA from glucose is generally not used to make ketone bodies, as glucose is a better “universal fuel”

56
Q

explain the metabolism of fatty acids in the liver

A

liver can also synthesize triacylglycerol from fatty acids, to be transported to adipose tissue for storage

  • acetyl CoA can be packaged into ketone bodies, ulimately want free FA in blood streamt but we bind these to serium albumin

**lok at figure more

57
Q

explain Hormonal regulation of metabolism

A
  • Hormone signal leads to modulation of protein function
  • hormone -> receptor -> regulated protein function
  • Peptide and amine hormones are generally faster acting than steroid & thyroid hormones

* 2 signalling pathways, cell surface receptors and nuclear recpetors

*peptides or amine hormones bind to receptor on outside of the cell: act through receptor w/o entering the cell

*nuclear receptor: steroid or thyroid hormone enters the cell: hormone- receptor complex acts in the nucleus

58
Q

what is teh well-fed state

A
  • Insulin signals that glucose levels are higher than required (4.5 mM in blood)
  • Insulin stimulates the liver, adipose tissue, and muscle to increase glucose uptake
  • It stimulates glucose transporters (GLUT4) to move to the membrane (responsible to take up glu into cell), needs to go to emmrbane to be acitvated

*insulin triggers GLUT4 transport to the membrane1

-Facilitate glucose entry into cells

It also stimulates increased glucose usage: inc glycogen synthesis, inc glycolysis, inc, pyruvate entry into the citric acid cycle, inc fatty acid biosynthesis in the liver, and storage in adipocytes

(inc stores of glucose in body)

59
Q

explain the fasting state

A
  • key organs are deprevied of energy
  • glucose levels, fall, pancrease generates glucagon sensed be liver, adipose tissue
  • TAG -> fatty acids which are released go to lvier, brocken down into ATP but also turn into ketone bodies which go to the brain can then generate ATP )brain cant break down FA)
  • adipose also send glycerol out, goes into gluconeogenesis goes to glucose-6-phos into glucose then into the brain
  • in extream fasting examples where adipose tissue energy sources are being deplated muscle proteins are brocken down to the liver turning into amino acids -> pyruvate then gluconeogenesis
60
Q

what is the active state

A
  • Epinephrine (= adrenaline) signals impending activity (flight or fight)
  • Acts on: muscle, liver, adipose tissue
  • In the liver: Stimulates release of glucose from stored glycogen
  • In muscle: Increases [fructose-2,6-bisPO4] → activates phosphofructokinase-1, stimulates glycolysis
  • In adipose tissue: stimulates release of fatty acids

**Epinephrine also: inhibits insulin secretion and stimulates glucagon secretion

61
Q

what happens during prolonged fasting

A
  • No more glycogen, so glucose must be made from amino acids
  • protein degradation form mucle yeilds gluconeogentic amino acids (not all aa can do this), go to liver and turned into some mol invovled in citric acid cycle
  • conversion of these amino acids has NH3 as by product, turns into urea and excreated
  • also have fatty aicds from adipose which makes acetyl CoA, generate ketone bodies to be sent to the brain
62
Q

what occurs in a stressed state

A
  • cortisol (steroid hormone) singals a stresed state including low blood glucose
  • is a slow acting hormone which alters the kinds and levels or metabolic enzymes
  • acts on liver and adipose tissue:

*Adipose -> release FA from TAGS

*Liver -> promotes gluconeogenesis, glucose is stoed as glycogen or exported

Net effect: restore blood glucose levels and increase glycogen stores

63
Q

what is diabetes

A

Diabetes is characterized by absence of ,or improper response to, insulin

Without an insulin response, metabolism is dictated by glucagon

As a result, even when glucose is abundant, it is not stored or used as a fuel

The organism “thinks” it is fasting, when it actually has excess glucose

nearly 7% of Canadian population has diagnosed diabetes

64
Q

what are the metabolic effects of diabetes (glucose)

A

In the liver, the concentration of Fructose-2,6- bisphosphate is kept low by an active FBPase- 2 phosphatase

  • DEC glycolysis
  • INC gluconeogenesis in the liver
  • GLUT4 glucose transporters are not moved to the membrane (muscle and adipose)
  • So sugar is not appropriately used or stored

Excessive blood sugar is secreted in the urine

65
Q

Metabolic effects of diabetes – fatty acids

A
  • Glucagon causes phosphorylation of Acetyl-CoA carboxylase, inactivating it
  • Acetyl-CoA accumulates in the cytosol, but is not converted into malonyl-CoA
  • So TAGs are not made and stored
  • Acyl-carnitine transport is highly active because malonyl-CoA concentration is low
  • Fatty acid β-oxidation increases, but oxidation is incomplete as high levels of NADH/NAD+ inhibits citric acid cycle
  • Excess acetyl CoA turned into excess ketone bodies
  • This can result in ketosis (excess ketone bodies) and acidosis (ketone bodies are acidic, lowering blood pH)
66
Q

explain regulation by GSK3

A

-GSK is used for the phosphorylation of glycogen synthase (inactivates it)

*when dont want to store

  • inhibited by insulin
  • glycogen synthase is activated by PPI, glucose, gluose 6 phos and INHIBITED by epinephrine and glucagon
67
Q

how does GSK3 work

A
  • have binding pocket, in order for enzyme to bind to glycogen synthase it has to bind via an already phos serine
  • prioir to GSK3 activity casin kinase must phosphorylate the seriine
  • GSK3 only binds if serine is already phosphorylated, domain the phosphorylates (like a stepping event, the next serine is phosphorylated and the enzyme steps to next)

***GSK3 can only phosphorylate a serine if the residue 4 C-terminal to it is a phosphoserine

68
Q

explain autoinhibition of GSK3

A
  • Glycogen synthase kinase 3 is auto-inhibited by a substrate-like sequence at its N-terminus
  • When phosphophorylated by PKB, this sequence binds in the catalytic site
  • Because the amino acid 4 upstream (0 site) is Pro, not Ser/Thr, the enzyme cannot further phosphorylate this sequence
  • Instead this pseudosubstrate just binds in the catalytic site, blocking real substrates

*

BIOC 3560 (11 decks)

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