Lecture 12 (2-26): Glycogen Flashcards
Glycogen: overview
- REGULATED
- globular, soluble polymeric form of glucose
- one multi-tiered or ‘tree-like’ structure that accommodates 20,000 to 30,000 glucose units
- units linked by 1,4 bonds - branching facilitated by 1,6 bonds
Glycogen: physical properties
- extremely hydrated (about 3x its own weight in water)
- since it is hydrophilic (saturated with water), it doesn’t pack as well as fatty acids
- 7-10% of residues are external - WHY??
Glycogen: components
- Glycogen typically found as granules
Core component is a beta particle:
- 2-5million Da in molecular weight
- 30 nm diameter
Alpha particle is large conglomerate of beta particles:
- 30 beta particles form a ‘rosette’
- 110 to 150 nm in diameter
- MW as high as 1,600,000,000 Da (this is HUGE)
Glycogen storage:
- Liver and muscle utilize glycogen differently
Glycogen stored in the liver:
- not stored for itself (uses mostly fatty acids as metabolic fuel)
- stored for other tissues (primarily the brain during short periods of fast)
- [Glycogen] varies: very low (0.1% of total liver mass) in fasting state, high (8%) in fed state
- stores good for about 1-2 days fasting
Glycogen stored in muscle:
- stored for itself - because massive quick access
- stores of about 1% muscle mass
- Glycolytic fuel for muscle when glucose or O2 is low
Glycogen supplements
- Contain: macroglycogenic nutrients, micro intracellular ergogenic substrates (most body can use to restore - 0.7g/kg; recommended - 76g for 240 lb person)
- All carbs, regardless of their original form, are broken down into single ring sugar structures, transported across the small intestine, stored in muscle and liver (THEN reassembled into glycogen)
- You COULD take glycogen supplements but biochemically, it doesn’t make much sense over simpler sugars for fast energy, dextrin for intermediate energy or complex carbs for long lasting energy
*Value is in Restocking Glycogen - consume 1.5g of high-glycemic carbs per 1 kg of body weight immediately after exercise
Control of Glycogen Metabolism
- Digestive breakdown is unregulated, but…. breakdown of tissue glycogen (important energy reservoir) is carefully controlled
- A highly regulated process, involving reciprocal control of glycogen phosphorylase (GP) and glycogen synthase (GS) allosterically
- Both enzymes are regulated in a way we haven’t seen before: covalent modification, phosphorylation
Breakdown of Tissue Glycogen: enzyme involved + process + type of reaction + metabolic advantage
Glycogen phosphorylase is the enzyme responsible for glycogen breakdown in the liver and muscle
- Glycogen is part of high MW “granules”
- — granules contain enzymes to break down or synthesize glycogen (CLEVER)
- Glycogen phosphorylase cleaves glucose from glycogen
- Note: this is a PHOSPHOROLYSIS, not a hydrolysis
Metabolic advantage: already one step into the glycolytic pathway
- product a sugar-P
- ‘charged’ (because it is phosphorylated)
- glycolysis substrate (sort of)
Phosphorylation of glycogen: how they discovered it, how it works
- covalent control
- Edwin Krebs and Edmond Fisher showed in 1956 that a “converting enzyme” converted phosphorylase b to phosphorylase a (P) (a phosphorylation)
- signal transduction: single ligand (adrenaline, hormones, etc.) stimulates massive response - cascade/amplification – binding at the surface/cell membrane stimulates production of cAMP which activates kinase which activates phosphorylase b kinase which converts phosphorylase b to phosphorylase a which converts glycogen -> glucose 1-phosphate
- phosphorylation causes conformational change
- Phosphorylation causes the amino terminus of the protein (res 10-22) to swing through 120 degrees, moving into the subunit interface and moving Ser-14 by more than 3.6 nm (and this leads to Conformational Change)
- Nine Ser residues on GP are phosphorylated
Breakdown of Tissue Glycogen: how it relates to the other glucose/glycogen processes
- Glucose-6-Phosphate is the branch point
- G6P –> glucose (to blood and brain)
- G6P –> pyruvate (via glycolysis)
- pyruvate –> G6P (via gluconeogenesis)
- G6P –> glycogen (via glycogenesis)
- glycogen –> G6P (via glycogenolysis)
Glycogen synthesis: purpose, control, enzyme
glucose 1-P –> glycogen (activating glucose for polymerization)
- involves Glycogen synthase a and Glycogen synthase b
- 5 Ser residues on GS are phosphorylated
- Glycogen synthase is the main enzyme involved
- protein phosphatase activated (-P)
- protein kinase A inactive (+P)
Glycogen Metabolism: breakdown overview
- activating glucose for polymerization
glycogen –> glucose-1-P
- phosphorylase kinase active (+P)
- protein phosphatase inactive
Type 1 Disorder - Glycogenosis (name, symptoms, type of deficiency)
- 1929 - von Gierke described autopsy of 7 yo girl and 5 yo boy with 3x liver size and 2x kidney size
- inherited as an autosomal recessive trait
- Glucose-6-Phosphatase deficiency
Symptoms of von Gierke’s disease (seen in first few months):
- massive hepatomegaly
- hypoglycemia*
- bleeding (nasal) - significant loss of blood
- retinal lesions
- lactic acidemia
- hyperlipidemia
- hypercholesteremia
- ketosis and ketonuria
- neutropenia
Type 1 glycogen Disorder - Glucose-6-Phosphatase deficiency (symptoms, traits, molecular defects)
Von Gierke’s disease
- G-6-Pase catalyzes final step leading to release of glucose into blood from liver
- Inability to do so -> increase [G-6-P] and accumulation of NORMAL glycogen in liver and kidneys - SIZE INCREASE
- Severity geography-specific: Syria and Lebanon (serious form of the disease), Saudi Arabia (mild form)
Molecular defects:
- Type 1a: Absence of activity of the catalytic subunit of glucose-6-Pase enzyme complex
- Type 1b: glucose-6-Pase transport
- Type 1c: microsomal phosphate or pyrophosphate transport
- Type 1d: microsomal glucose transport
Type II Deficiency: Glucosidase deficiency (name, symptoms, traits, molecular defect)
- In 1932, Pompe describe a 7 mo girl who died of idiopathic hypertrophy of the heart (POMPE DISEASE)
- most devastating of the glycogen storage diseases
- affects all cells but primary effects in the heart and skeletal muscle
Two types:
- Infantile (Pompe’s disease): Presents early with weakness/respiratory distress; Cardiac failure within first year
- Juvenile form: milder - gait problems in 2nd-3rd decade
Molecular defect:
- Lack of alpha-glucosidase, which is present in lysosomes - capable of function at acidic pH
- Not a regular enzyme in glycogen metabolism (but capable of breaking down glycogen at an acidic pH)
- —- main function: hydrolyze linear oligo as well as outer branches of glycogen to yield free glucose
Type V: Muscle Phosphorylase deficiency (name, symptoms/traits, molecular defect)
McArdle Disease
- In 1951, McArdle described a 30yo man with muscle weakness, muscle pain/cramps and stiffness after brief exercise
- ——- blood lactate levels fell during exercise!!! (what’s up with that?)
- Proposed a deficiency in the enzyme(s) that breaks down glycogen
Molecular defect:
- deficiency of muscle phosphorylase demonstrated (1957)
- the muscle pain is from a build up of muscle ADP
Key observations:
- liver glycogen phosphorylase normal
Type VI: Liver Phosphorylase deficiency (symptoms, defect, traits)
- Patients with this deficiency have symptoms similar (but less severe) to the von Gierke’s (type 1) disease
- —– blood lactate levels fell during exercise
Molecular defect:
- no LIVER phosphorylase
Key observations:
- hypoglycemia the result of inability to utilize glycogen to generate glucose
Pentose Phosphate Pathway: how it starts/relates to other processes
aka hexose monophosphate shunt
- Glucose-6-P is branch point: can go through glycolysis or be converted to Glu-1-P (to glycogen for energy storage in liver and muscle or for CHO synthesis) or can go to PPP
Pentose Phosphate Pathway: location + purposes of both phases
- operates mostly in cytoplasm of liver and adipose cells
The Oxidative phase: produces NADPH
- NADPH is the SECOND CURRENCY OF THE CELL
- fatty acid synthesis
The Non-oxidative phase: produces 5-C sugars
- DNA/RNA
- glycolytic intermediate
- Oxidation of glucose: but role focused on ANABOLIC process not CATABOLIC
Pentose Phosphate Pathway: oxidative phase (location, net effect, reactions)
Glu-6-Phosphate DH: steps 1/2
- dehydrogenation
- hydrolysos
6-P-Gluconate DH: Step 3
- oxidative decarboxylation
- Operates mostly in cytoplasm of liver and adipose cells
- NADPH is used in cytosol for fatty acid synthesis
Net effect of Oxidative phase:
+1 CO2
-1 H2O
+2 NADPH
Pentose Phosphate Pathway: non-oxidative phase (location + net effect)
- also Operates mostly in cytoplasm of liver and adipose cells
- REGULATION?
Net effect of non-oxidative phase:
- Ribose-5-phosphate produced for DNA/RNA building
Overview of steps of PPP Oxidative phase
- Glucose-6-P Dehydrogenase: irreversible 1st step - highly regulated!
- Gluconolactonase
- 6-Phosphogluconate Dehydrogenase: oxidative decarboxylation
Overview of steps of PPP Non-oxidative phase
- Phosphopentose isomerase: converts ketose to aldose
- Phosphopentose Epimerase: epimerizes at C-3
- /8. Transketolase (TPP-depend.): transfer of 2-carbon units
- Transaldolase (Schiff base mechanism): transfers a 3-carbon unit
PPP: NADK
- NADK is highly regulated (allosteric by NADH/NADPH)
- NAD primarily in NAD+ form
- NADP primarily in NADPH form
- NADK can modulate responses to oxidative stress by controlling NADP synthesis
Due to the essential role of NADPH in lipid and DNA biosynthesis and the hyper proliferative nature of most cancers, NADK is an attractive target for cancer therapy
Biological Lipids: definition, functions
Biological molecules that are insoluble in aqueous solutions and soluble in organic solvents are classified as lipids. The lipids of physiological importance for humans have four major functions:
- They serve as structural components of biological membranes
- They provide energy reserves -> triacylglycerols
- Both lipids and lipid derivatives serve as vitamins and hormones
- Lipophilic bile acids aid in lipid solubilization
Fatty acids: definition, major roles
Fatty acids are long-chain hydrocarbon molecules containing a carboxylic acid moiety at one end
Fatty acids either contain:
- no C-C double bonds (Saturated)
- double bonds (unsaturated)
Fatty acids fill two major roles in the body:
- as the components of more complex membrane lipids
- as the major components of stored fat in the form of triacylglycerols
Fatty acids or glycogen: Better form of energy storage? Which one?
- Fatty acids better because they can pack more chains into small space and (1) extent of reduction (2) tighter packaging
Why fatty acids for energy storage?
Two reasons:
1) Extent of Reduction:
- The carbon in fatty acids (mostly CH2) is almost completely reduced
- Oxidation yields the most energy possible
2) Tighter packaging:
- Fatty acids are not hydrated like mono- and polysaccharides
- They pack more closely in storage tissues
- Compare with glycogen
What is a glycogenin?
an enzyme involved in converting glucose to glycogen
- a glycosyltransferase that acts as a ‘primer’, by polymerizing the first few glucose molecules…. THEN other enzymes take over
- it catalyzes the chemical reaction
Fat from diet and adipose cells: Triacylglycerols (TAGs) either way (importance, link to disease)
- Triglycerides represent the major energy input in diet
- Triglycerides are also the major form of stored energy in the body
- Stored in globules in fat cells (adipocytes)
- – excess fat is stored in lipocytes, which expand in size until the fat is used for fuel
Visceral fat: has been linked to metabolic disturbances and increased risk for cardiovascular disease and type 2 diabetes. In women, it is also associated with breast cancer and the need for gallbladder surgery
Does obesity come with more fat cells?
- Original thought: grow new fat cells during 1st year and puberty, fat cells just increase in size with weight gain
- New data indicates that we can create new fat cells as adults - harder to lose weight? Once they are there, fat cells may never go away
Has our view of fat changed?
Triglycerides the major energy input in the modern American diet:
- average diet: 30-60% calories obtained from FA
- good fats - PUFAs
- bad fats - saturated fats, trans fats
Excess dietary fat:
- weight problems -> obesity, disease
- – not something that should be selected for by “natural selection” - not the “fittest”
Fat as an energy source: specific grams/%
Fat provides most energy per unit weight!! (sort of… linked to reduced state)– BIGGEST KICK per gram
- fat: provides 37 kJ of energy***
- protein: 17 kJ
- glycogen: 16 kJ
- glucose: 16 kJ
Mass!
- fat: 15,000 g - 83% of stored energy**
- protein: 6,000 g. - 15% of stored energy
- glycogen: 190 g - 0.5% of stored energy
- glucose: 20g - 0.0004% of stored energy
Of the total available energy (660,360 kJ): 555,000 kJ from fat
- makes sense for evolutionary conservation of fat
PPP Oxidative Phase: Regulation
Regulation:
- Glu-6-Phosphate DH rate limiting enzyme:
- –Ratio of NADPH/NADP+ is about 100:1 in liver
- – Allosteric (+) NADP+
- – makes sense: when processes that use NADP+ increase in activity, NADPH decreases (and NADP+ increases) which tells the enzyme to make more NADPH
Why the evolutionary conservation of fat?
So why the evolutionary conservation?
- vast majority of the energy we store is in fat
- efficiency: fat makes up 83% of total energy storage (highly reduced state of carbon, mass)
- to evolve glycogen as best stored source, would need 180x the glycogen currently found in the liver and muscle
So why the evolutionary conservation?
- Efficiency: the ‘one-two punch’ that fat packs (83% of total energy!)
- — highly reduced state of carbon
- — mass
- Why not evolve glycogen as the best stored source?
- — have the equivalent energy stored in glycogen
- — need 180x the glycogen currently found in liver and muscle…. weight of glycogen needed? about 36 kg = about 79 lbs added to total weight
