Chapter 21 (Glycogen Synthesis and Degradation) Flashcards
Where does Glycogen metabolism Occur
- Liver
- Skeletal Muscles
Overall enzyme deficiencies in glycogen metabolism
Leads to problems in Liver + muscles = they don’t function normally
- Can create issue in diaphragm = THEN have large problem –> get lung problem – lungs get infected = can die from infection
What type of muscle is the diaphragm
Skeletal muscle – if have issue in glycogen metabolism = then can have issue in diaphragm because its a skeletal muscle that relies on glycogen metabolism –> issue in diaphragm can cause lung infection = can die
Structure of Glycogen
Glycogen is a highly branched homopolymer of glucose
- Has Alpha 1,4 and Alpha 1,6 bonds
- Has a reducing and a non-reducing end (non-reducing ands have free OH group)
***Glycogen molecuke has 12 layers of flucose molecules – can have 55,000 glucose residues
- Most of the glucose is linked by 1,4 bonds BUT it is branched every 12 residues by 1,6 bonds
- Alpha glycolidic links can form helical polymers
Where is glycogen found
Found in the cytoplasm of all tissues
Middle of the Adrenal gland
Medula
What does the Medula release
Catacolin – Catacolin = epinerphrine + Norepinephrine
Where are the largest stores of Glycogen
Liver + Skeletal mucles
Liver + glycogen
Liver breaks down glycogen and releases glucose into the blood to provide energy for the brain and Red Blood Cells
Skeletal Muscle + Glycogen
Skeletal Muscle glycogen stored are used to provide energy for muscle contraction
***ATP helps Myosin + Actin connect = contract muscle
Glycogen degradation steps
- Release of Glu-1-P from glycogen
- Remodeling of Glycogen to allow for continued degradations
- Conversion of Glu-1-P into Glu-6-P
Fates of Glu-6-P
- Processing by the Glycolytic pathway
- Conversion into free free glucose for release into the blood
- Mainly occurs in the liver - Precessing by the Pentose Phosphate pathway (Produces NADPH)
Glycogen metabolism is…
The regulated release and storage of Glucose
What is required for Glycogen synthesis
requires an activated form of glucose – UDP-Glucose
What is an activated form of Glucose
UDP-Glucose
How is UDP-Glucose formed
Formed by the reaction of UTP and Glu-1-P
Regulation of Glycogen degradation and synthesis
Glycogen degradation and synthesis are reciprocally regulated
***Regulation of glycogen degradation is complex
Issue with glucose
Glucose is an important furl BUT glucose can’t be stored because high concetaryions of glucose would disprut the osmotic balance –> would cause cell damage or death
Solution: Store glucose as non-osmotocally active glycogen
Glycogen
readily mobilized storage form of glucose
Use of glycogen
Can be broken down to yield glucose when energy is needed
Glycogen vs. FA
Glycogen = not as reduced as Fatty Acids = not as energy rich
Why isn’t all excess fuel stored as FA rather than glycogen
Controlled release of glucose from glycogen = maintains blood-glucose concentration between means –> circulating blood keeps the brain supplied with glucose –> glucose is used by the brain as fuel
- Readily mobilized glucose from glycogen = good source of energy for sudden activity
+ Unlike fatty acids – the release pf glucose can occur without Oxygen = can supply energy in aerobic environment
***Couldn’t have the same effect with FA
What organisms have Glycogen
Archea + Bacteria + Euk
**Plants = store glucose as starch
**Storing glucose as a homopolymer is common in all life forms
Amount of glycogen in Muscles vs. liver
Higher concentration of Glycogen in muscles BUT there is more glycogen stored in skeletal muscles overall because muscles make up more mass
Use of Glycogen Synthesis and degradation
Liver –> Glycogen synthesis + degradation is used to maintain blood-glucose levels
Muscle –> Glycogen synthesis and degradation is used to regulate energy need in muscle itself
When does glycogen synthesis occur
Occurs when glucose is abundant
Why is glycogen regulation complex
Partly because all of the enzymes involved in glycogen metabolism + its regulation are associated with glycogen particle
Glycogen metabolism (overall)
- Several enzymes in glycogen metabolsim = allostarically respond to metabolites that singla energy needs of the cell
- Hormones can intiate signal cascade that leads to reversible phosphorylation = alters catalytic sites
Hormone reductions + glycogen metabolism
Reduction of hormones adjust glycogen metabolism to meet the needs of the organism
Glycogen Phosphorylase
Degrades glycogen from the non-reducing end
- Phosphorylase catalyzes a phsphorylsis reactions that yields glucose-1-P ***Creates Glucose-1-P
Reactions: Glycogen (n) + Pi –> Glu-6-P + Glycogen (n-1)
Phosphoglucomutase
Converts Glucose-1-P to Glucose-6-P
***Does not use ATP
Requirements for Glycogen Phosphorylase
Requires Pryidoxal Phosphate (PLP) cofactor
Use of PLP
Required for Glycogen Phosphorylase
Use – forms Schiff base with a Lysin residue at the active site of phosphorylase
***Requires Lysine
Glycogen –> Glu-6-P enzymes activties
Requires 4 enzyme activities
- 1 enszymes to Degrade glycogen
- 2 enzymes to Remodel Glycoegn
- 1 enzyme fo convert the product of glycogen breakdown into a form sutable for metabalism
Hey enzyme in glycogen vreakdown
Glycogen Phosphorylase
How does Glycogen Phosphorylase work
Cleaves substate by adding Pi –> yeilds Glu-1-P
Phosphoprylysis
Cleavage of a bond by adding Pi
***done by glycogen phsophorylase
Glycogen phosphorylase (Textbook)
Catylzyes the sequental removal of glycosyl group of the non-reducing end of glycogen molecule
**Pi splits the glycosidic link betwen C1 of the terminal residue and C4 of the adjacent one
**retains the alpha configuration
***Cleaves bond between C1 and glycosidic Oxygen
Reversibility of the phosphorylase reaction
Phosphorylase reactions is readily reversible
pH = 6.8 –> ratio of Pi to glucose is 3.6
dG = very small because of the glycosidic link is replaced by a phosphoryl etser nond that has equal transfer potential
BUT phosphorylysios prcoeeded in foward directions of glycogen breakdown because the Pi/Glu-6-P ration is >100 = favors phosphorylysis
Why does phosphoylysis go fowards
Phosphorylysis proceeded in forward directions of glycogen breakdown because the Pi/Glu-6-P ration is >100 = favors phosphorylysis
***Shows cells ability to alter delta G to favor reaction occurance by altering ratio
Energy of Phosphpylysis
Phophorylitic cleavage of glycogen = energetically favoarbey becayuse released sugar is already phosphorylated
VS.
if it used hydrolytic activity –> then it would yeild a glucose –> the glucose would then have the be phosphorylated at the expense of ATP
Issue if Phosphorylase
Cleaving the glycogen with phosphate rather than hydrolitically means that water needs to be excluded from the active site
Structure of phosphorylase
Dimer with idetical subunits
- each Sub unit os completley folded into amino terminal domain containing a glycogen binding site and an carboxy terminal domain
- the catalytic site in each sub unit = located in the deep crevice formed by residues from both domains - Substrates bind at the same time = causes the creavice to narrow
***Structure is done this way in order to exclude water
Clues that suggest mechanism of phosphorylase
1 – both glycogen and Glu-1-P have alpha at C1 –> IF there was a direct attack of Phophate at C1 then there would be inversion of configuaration at the carbon because the reaction woudl proceed via penta covalent intermediate
BUT we know that Glu-1-P formed has alpha configuration = suggests that there is an EVEN number of steps
- LEADS to likley explination that there us a carbocation intermediate
2 – Mechanism requires a coenzyme PLP – the aldehyde on the coenzyme = forms a schiff base link with Lysine in enzyme
- Studies show that the Pi takes the position between the 5’ phosphate of PLP and glycogen substrate
- Pi donates H+ to oxygen on C4 of glycogen + at the same time aquires a H+ from PLP
- carbocation intermediate = attacked by Pi = get Glu-1-P + return PLP
PLP vitamin
PLP is a derivative of B6
Glycogen binding site in Phosphorylase
Glycogen binidng site is 30A away form the catalytic site BUT it is connected to the catalytic site by a narrow crevice that can fit 4-5 glucose units
Seperaration between catalytic site and binding site in Phosphorylase
Enables the enzyme to phosphorylate many resides without having to dissociate and reassociate after catalytic cycle
Processive enzyme
Enzyme that is able to catyluze many reactions without having to dissciate and reassociate after each catalytic cycle
Example – phosphorylase
***Property of enzymes that synthesize and degrade large polymers
Use of PLP in phosphorylase
The phosphate substrate promotes the cleavage of a alpha 1,4 bond in glycogen by donating a proton to the departing glucose –> results in a carbocation intermediate
Intermediate in phosphorylase mechanism
Carbocation intermediate – carbocation intermediate and phosphate combine to form Glu-1-P
1,4 bonds vs. 1,6 bonds
1,4 bonds = don’t break easily
1,6 bonds = break easier
Amino Acids in Glycogen Phosphorylase
- Lys 680
- Gly135
- Gly134
- Arg 569
- Lys 568
***Also uses a PLP
Schiff base Alternative name
Schiff base = Iminie
Schiff base formation
Schiff base is formed by the reaction of a primary amine with an aldehyde or a Ketone
PLP- forms a schiff base with lysine in phosphorylase active site
Phosphorylase Mechenism (Image)
Second enzyme needed for glycogen breakdown
A debranching enzyme
Limitation of Phosphorylase
Phosphorylase acting alone = degrades glycogen to a limited extent –> it can break 1,4 bonds BUT it can’t cleave 1,6 Bonds
***Alpha 1,6 bonds are not sucetable to Phosphorylase
- phosphorylase stops cleaving 1,4 links when it reaches terminal residue 4 residues away from branch point
- Because 1 in 12 residues = bracnching residue – clevage by only phosphorylase alone would come to a later after 8 glucse residues per branch
How is the remainder of glycogen molecule mobilized for use as fuel
After phosphorylase – have transferase + Alpha 1,6 glucosides
Transferase + Alpha 1,6 glucosides
remodel glycoegn – allows form continued degradation by phosphorylase
***Can remodel –> then phosphorylase can keep working
Transferase
Shifts a block of 3 glycogen residues from outter branch to another
- Transferase exposes a single glusode resiude joined by Alpha 1,6 bonds - Transferase = shifts a small oligiosaccaride near a branch point to a neaby chain --> therebu making the glucose moeities accesible to phosphorlase
Glycogen remodeling
- Transferase – Shifts a block of 3 glycogen residues from outter branch to another –> Transferase exposes a single glusode resiude joined by Alpha 1,6 bonds
- Alpha glucosidease = hydrozlyses the 1,6 bond
THEN phosphorylase can keep working
Overall – 1,6 Glucosidase + transferase convert branched structured into linear –> paves the way for further clevage by Phosphorylase
Alpha 1,6 glucosidease
Debranching enzyme – hydrolyzses 1,6 bonds
- Clevase the 1,6 bonds at the branching point = releases a free glucose - Uses a Water
***The free glucose is relases and can be phosphorylated by hexokinase to go to glycolysis or to PPP
Transferase and 1,6 glucosidase in Euk
In Euk – they are present in one polypeptide chain = they are a bifunctional enzyme
Glycogen remodeling (image)
Phosphoglucomutase
Converts Glu-1-P to Glucose-6-P
***Causes shift in phosphate group
Active site of Phosphoglucomutase
Conatains a Phosphorylated Serine in the active site
Intemediate of Phosphoglucomutase
Phosphoglucomutase forms a Glucose 1,6 bisphosphate intermediate
- Forms the intermediate by donating its bound phosphoryl group to Glucose-1-P
- The phosphoryl group is restored to the enzyme with the formations of Glu-6-P
Phosphoglucomutase reactions (image)
Next steps after Glu-1-P is formed
Onces Glu-1-P is formed –> needs to be converted to Glu-6-P to enter the metabolic mainstream
Phosphoglumutase reaction (depth)
The enzyme adds phostphate to Glu-1-P at the cataklytic site (done so because have a phophate on Serine resiude at the catalytic site) – the phosphorylk group is transfered from Serine to the C6 OH of Glu-1-P = forms Glu-1,6-BP
THEN C1 phosphate group = shyttled to the serine reidude –> donates the phosate at C1 to the Serine residue –> form Glu-6-P + regernates the phosphorylated enzyme
What is found in the liver that is absent in the Muscle
Liver contains a hydrolytoc enzyme Glu-6-Phaphatse that is not found in the muscle
Glu-6-Phosphatse
Glu-6-P –> Glucose
***Found in teh liver
Reaction – Glu-6-P + water –> Glucose + pi
**Free glucose is relased into the blood for use by other tissues such at the brain and RBCs
**Same enzyme that relases free glucose at the end of glucogenssis
***Located in the lumen side of the SER membrane – Glu-6-P goes to the ER –> Glu + Pi –> Leave cell
Glu-6-Phosphatse throughout the body
Glu-6-Phosphatse = absent from most other tissues
Glu-6-P in mucles
Muscle tissues retain their Glu-6-P for ATP syntehsis
***NO ATP = the muscle won’t contract
What is needed for muscle contraction
ATP + Ca2+
Glucose in muscle vs. liver
Muscle –> Glucose-6-P = used to generate ATP
Vs.
Liver –> Glucose is not the major fuel for the liver
Fuel for the brain
Glucose
What if you have an issue in smooth muscles
Bad for blood flow
Major function of the Liver
To maintain a nearly constant concentration of glucose in the blood
***Role = to form glucose to exprot to other tissues when blood glucose concentration is low
Liver = releases glucose into the blood between meals + during musclular activity
Released glucose from liver
Taken up porimarly by the brain + skelatal muscles + RBCs
Phosphorlated glucose made from glycogen degradation in liver
NOT trasnprted out of the cell –> liver needs to convert it to Glucose to be able to release it = has Glu-6-Phosphatse to be able to do so
How is phosphorylase regulated
- Allosteric Interactions – signla energy state of cell
- Reversible interactions – responsive to hgromones (Insulin + epinepherine + Glucogon)
Key regulatory enzyme in Glycogen degradation
Glycogen Phosphorylase
***Glycogen degradation = orecicley contrilled by multpple interlocking mechanisms BUT the focus of control - Glycogen phosphpylase
Forms of Glycogen phosphorylase
- B form –> LESS active
- A form –> MORE active
A form vs. B form
A from = has a phosphorylated Serine residue
***Makes it MORE active
A form = exhibits most responsible R –> T transition
Equillibruim of A form and B from
Both in equillibrium between R and T states
BUT
B form –> T starte is favored (Tense = Less active)
A form –> R state is favored (Relaxed = active)
Liver regulation vs. Muscle regulation
They are regulated differentley because liver maintains glucose homeostasis of the organism but the muscle uses glucose for energy for itself
Key role of liver
To maintain adequate blood glucose levels
Default state of liver Phosphorylase
a from –> R state
***Liver phosphorylase is prepared to generate blood glucose unless signalled otherwise (because its always in the active A form)
Glucose as a regulator for Liver phosphorylase
Glucose is a negative regulator for liver phosphorylase –> facilitates the transition from R state to T state (Active –> Inactive)
Have Glucose = in the T state (glucose puts it in the T state = inactive)
**Enzyme reverts to T state only if it senses the presence of sufficient glucose
**If glucose is present in diet then there is no need to degrade glycogen
Liver phosphorylase vs. Muscle phosphorylase
Isozymes
How is Muscle phosphorylase regulated
Regulated by Intracellular energy charge
Default form of Phosphorylase in Muscle
b form –> in the T state
***Because the phosphorylase must be active during muscle contraction
Regulation of Muscle phosphorylase
When energy is needed (Increase in AMP) –> Phosphorylase binds to AMP = stabilizes the phosphorylase in the R state = active = degrades glycogen
- B form is Activated by increase in AMP –> AMP binds to the nucleotide binding site = stabilized teh confirmation of B in the R state = active – means that when a muscle contracts and ATP decrease –> AMP binds –> phosphorylase is signalled to degarde glycogen (uses Mysin + Adenylate Kinase)
VS.
T state = stabilized by ATP and glu-6-P = won’t degrdae glycogen
- When ATP is unavalble – Glu-6-P may bind to the ATP binding spot = stabilizes in the less actove form = feedback inhibition
- In resting states B = inactive bevause of inhibtor affects of ATP and Glu-6-P BUT a form is fully active regardless of concentration of AMP,ATP, and Glu-6-P
Liver Glu-6-P + AMP
Glucose-6-Phosphatse = insenstive to regulation by AMP because liver does not undergo dramatic chnages in Energy charge
What does the differnce in regulation of liver vs. muscle isozyme show?
Shows exmaple of the use of isozymes to establish tissue specific biochemical properties of liver + muscle
***Isozymes = 90% idetical in AA sequence yet 10% difference is subyle but improitant shift in regualtion
Three types of skeletal muscles
- Type 1 –> Slow twitch
- Type 2b –> Fast twitch fibers
- Type 2a –> Intermediate between types
Type 1
Slow twitch fibers –> use cell respiration powered by FA degradation to generate ATP
***Glycogen is not an important energy source for these fibers – has lower amounts of glycogen phosphotase
- relies of CR
- Powered by FA degradation
- Rich in mitocondria
- powers endurace
FA = good energy storage form BUT generating ATP from Fatty acids is slower
Type 2b
Fast-twitch fibers – generate energy by aeorobic glycosis + prefrom little Cell respiration
***Mitocondria are rare and glycogen is the primary fuel for them
- Glycogen = main fuel –> have more glycogen Phosphorylase
- Fibers are rich inglycolitic ensymes –> needed to process glucose quickly in absense of Oxygen
- Poor in mitocndira
- Powers burst activities
Type 2a fibers
Process properties intermediate between the two fibers
Converting between muscle types
No amount of training can interconvert type 1 and Type 2b BUT type 2a is trainable
FA as a fuel
FA = good energy storage form BUT generating ATP from Fatty acids is slower
Biochemical properties of muscle fiber types
