glucogenesis and glycogen metabolism Flashcards
what tissues require a continuous supply of glucose as a metabolic fuel
Brain
- Uses 120g of glucose per day
Red blood cells
Kidney Medulla
The lens and the cornea of the eye
Testes
Exercising muscle
how much glucose is in the body - in glycogen stores and in blood
~190g from Glycogen stores
~20g circulating in the blood
In the absence of dietary input, liver glycogen can only meet demand for how many hours
10 - 18hrs
once body stores of glucose are depleted glucose is formed from what precursors
Lactate
Pyruvate
Glycerol (from triacylglycerol breakdown - mammals cannot synthesise Glucose directly from fatty acids)
α-ketoacids (from amino acid breakdown) = some of the amino acids that make up proteins
is pyruvate to glucose called reverse glycolysis and why
Sadly not…
Due to the 3 irreversible reactions in Glycolysis this cannot occur, thus glucose is synthesised in a unique pathway
So Gluconeogenesis is done
what is gluconeogenesis
the formation of Glucose from non-carbohydrate sources
(pyruvate to glucose)
how much of gluconeogenesis occurs in the liver
90%
Kidneys provide what percentage of newly synthesised glucose molecules and whats their role in Gluconeogenesis
10%
they play a minor role except in prolonged starvation, when they become major glucose producing organs
what reactions are unique to gluconeogenesis
3 irreversible reactions:
- Glucose –> Glucose-6-phosphate (Hexokinase)
- Fructose-6-phosphate –> Fructose-1,6-bisphosphate (phosphofructokinase)
- Phosphoenolpyruvate —-> Pyruvate (Pyruvate kinase)
In gluconeogenesis 4 alternate enzyme catalysed reactions are used to circumvent the 3 irreversible steps
- Bypass 1 – Pyruvate kinase = 3 steps
- Bypass 2 – Phosphofructokinase = 1 step
- Bypass 3 – Hexokinase = 1 step
Other reactions are a reversal of glycolysis
explain bypass 1 - pyruvate to phosphoenolpyruvate step 1
Step 1: Carboxylation of Pyruvate:
Pyruvate —> Oxaloacetate by the enzyme Pyruvate carboxylase
- Pyruvate carboxylase is only found in the mitochondria of LIVER and KIDNEY cells, so why it only occurs in these cells
explain Bypass 1: Pyruvate to Phosphoenolpyruvate step 2
Oxaloacetate, formed in the mitochondria, must enter the cytosol where the other enzymes of gluconeogenesis are located
However, oxaloacetate is unable to cross the inner mitochondrial membrane directly
- It is first converted into malate by the enzyme mitochondrial malate dehydrogenase
- Malate can cross the mitochondrial membrane, where is it then re-oxidised back into oxaloacetate by cytosolic malate dehydrogenase
Basically were going from oxaloacetate to oxaloacetate in another area by converting it to malate and back to oxaloacetate
Decarboxylation of cytosolic oxaloacetate:
Oxaloacetate isdecarboxylatedand phosphorylated in thecytosol byphosphoenolpyruvate. carboxykinase(PEP-carboxykinase).
- Reaction is driven by the hydrolysis of GTP.
- PEP then enters the reversible reactions of glycolysis until itreaches fructose 1,6-bisphosphate.
explain bypass 2: Fructose-1,6-bisphosphate to Fructose-6-phosphate
Dephosphorylation by hydrolysis of fructose1,6-bisphosphate bypasses the irreversiblephosphofructokinase reaction of glycolysis and is catalysed by the enzyme Fructose bisphosphatase - this takes one of the phosphates away
The reaction is an important regulatory site ofgluconeogenesis.
explain Bypass 3: Glucose-6-phosphate to Glucose
Hydrolysis of glucose-6-phosphate by glucose-6-phosphatase bypasses the irreversiblehexokinase reaction of glycolysis.
Glucose 6-phosphatase is present in the LIVER andKIDNEY, but not in muscle.
what is the Tissue location of glucose 6-phosphatase and pyruvate carboxylase
Glucose-6-phosphatase and Pyruvatecarboxylase occur in cells of the the liver and kidney, but notin muscle.
- Thus, muscle cannot contribute to blood glucoseby gluconeogenesis, nor can it produce glucosefrom glucose 6-phosphate derived from muscleglycogen.
- Only liver (and kidney) can contribute to the bloodglucose pool.
what are Gluconeogenic precursors
molecules that can give rise to anet synthesis of glucose.
what do substrates for Gluconeogenesis include
all the intermediates of glycolysis and the citricacid cycle.
what are the most importantgluconeogenic precursors obtained from thedeamination of glucogenic amino acids
Glycerol,
lactate
and the⍺-ketoacids
explain the substrate - glycerol, for Gluconeogenesis
Is released during hydrolysis oftriacylglycerolsin adiposetissue and is delivered in the blood to the liver.
Glycerol is phosphorylated to glycerol phosphate, which isoxidised to the glycolytic intermediate,dihydroxyacetonephosphate.
- Dihydroxyacetone phosphate —> Glyceraldehyde-3-phosphate
- Triose phosphate isomerase
explain the substrate - lactate, for glucogenesis
Is released into the blood by cells that lack mitochondria, suchas red blood cells and by exercising skeletal muscle.
In theCori cycle, blood-borne glucose is converted byexercising muscle to lactate, which diffuses into the blood.
This lactate is taken up by the liver and converted to glucose,which is released back into the circulation.
In exercising muscles, a lot of lactate is produced
explain substrate - alpha-ketoacid, for gluconeogenesis
Amino acids whose catabolism yields pyruvate or one of theintermediates of the citrate cycle are called glucogenic (orglycogenic).
These intermediates are substrates for gluconeogenesis andtherefore can be used to contribute to liver glycogen in liverand muscle.
The body has developed mechanisms for storinga reserve pool of glucose in the form of what
glycogen
what happens When glycogen stores are depleted
the body thensynthesises glucose by gluconeogenesis in the first instance.
Dietary intake of glucose and the precursors of glucose iswhat
sporadic,and a constant source of blood glucose is of absolute metabolicimportance.
(Our bodies need glucose)
explain the amounts of liver and muscle glycogen
About 400g of glycogen makes up 1-2% of the fresh weight ofresting muscle and about 100g glycogen makes up the freshweight of a well-fed adult liver.
What limits the production of glycogen at these levels is notknown.
explain glycogens structure
Glycogen is a branched chain homopolysaccharide madeexclusively from⍺-D-glucose.
They have reducing and non reducing ends
The primary glycosidic bonds are⍺1-4 and between every 8-10 residues there is a branch consisting of an⍺1-6 glycosidicbond.
Glycogen molecules can have a molecular weight ≤ 108. Theyexist as discrete cytoplasmic granules containing most of theenzymes for synthesis and breakdown
what is glycogen granule
The core is made up of the protein Glycogenin, and is surrounded by the branches of Glucose polymers
Glycogen molecules are big
Due to the alpha 1 – 6 bonds, its very dense so more glucose can be in the same space
what is glycogen synthesis
The process occurs in the cytosol, and requires energy suppliedby ATP (for the initial phosphorylation of glucose) anduridinetriphosphate (UTP).
glycogen in glycogen synthesis is synthesised from what
molecules of⍺-D-glucose that areinitially attached touridinediphosphate(UDP).
(UDP is like ADP etc)
explain glycogen synthesis step 1: Synthesis of UDP-Glucose
Glucose attached touridinediphosphate(UDP-glucose) isthe source of all glucosyl residues that are added to thegrowing glycogen molecule.
First, glucose 6-phosphate is converted to glucose 1-phosphate byphosphoglucomutase
Cant have glycogen without glycogenin
explain glycogen synthesis step 2: Synthesis of a Glycogen primer to initiate Glycogen synthesis
The main enzyme involved in glycogenpolymerisation,glycogensynthaseis responsible for making the⍺1-4linkages inglycogen.
However, this enzyme can only add to an existing chain of between5 to 8 glucoseresidues.
Thus, glycogen synthesis requires a primer, a role that is carried outbyglycogenin
what is glycogenin structure
Dimer of 2 identical 37kDsubunits
what does glycogenin catalyse
catalyses the addition of glucose to itself bycovalently attaching glucose from UDP-glucose to the hydroxylgroup of tyrosine-194 in eachsubunit.
This is an autocatalytic reaction facilitated byglycogeninitiator synthaseactivity
Glycogeninalso has______activity which allows what
glucosyltransferaseactivity
which allowsthe addition of up to 8 glucose residues from UDP-glucose toits partner in theglycogenindimer in this sequence ofautoglycosylations.
explain glycogen synthesis step 3: Elongation of Glycogen chains by Glycogen synthase
Elongation of a glycogen chain involves the transfer of glucosefrom UDP-glucose to the non-reducing end of the growingchain.
The enzyme responsible for making these⍺-1,4 linkages inglycogen isglycogensynthase
UDP released when the new⍺-1,4 linkage is formed can beconverted back to UTP by thenucleosidediphosphokinase
UDP + ATP UTP + ADP
The Glycogen branching enzyme (amylo-⍺(1:4)→⍺(1:6)transglycosylase) transfers the end of one chain to an earlier part of the chain by a 1,6-glycosidic bond
