Carbohydrate Metabolism: G6P and Glycogen

• These study notes cover newer material in the course

Exam Details

• The final exam is on Thursday
• There will be 65 questions
• Remember to bring a scantron, an ID, and bubble in the version on the scantron
• There will be an old material refresher on Wednesday night from 5-6PM, and older material is still a good portion of the exam

Glucose-6-Phosphate (G6P)

• G6P is a key branching point for carbohydrate metabolism.
• It serves as a precursor in:
• Gluconeogenesis (GNG) via glucose-6-phosphatase
• Glycolysis via phosphoglucoisomerase
• Glycogen storage via phosphoglucomutase
• Pentose Phosphate Pathway (PPP), converted by Glucose-6-phosphate dehydrogenase.

Glycogen

• Glycogen provides a means to store glucose in the body.
• It is a polymer chain of glucose that can be cleaved off during glycogenolysis to produce glucose when glucose levels are low
• Glycogen contains α-1,4-glycosidic bonds between glucose molecules and α-1,6-glycosidic bonds at branching points.
• Highly branched structure facilitates rapid energy release when compared to plants
• Reducing end: where glycogen formation originally started
• Glucose molecules are released from the non-reducing ends

Glycogen Synthesis

• Glycogen synthesis occurs when there’s plenty of glucose and readily available energy
• Glycogen synthesis is an example of anabolism: taking in smaller subunits with energy to form longer subunits.
• Insulin serves as the signal for glycogen synthesis. Insulin is a hormone made in pancreatic beta cells that allows exocytosis of GLUT4 receptors
• Insulin facilitates glycogen and fatty acid storage
• High-carbohydrate diets increase insulin levels, activating fatty acid biosynthesis in the liver when insulin activates Acetyl-CoA carboxylase
• Acetyl-CoA carboxylase converts Acetyl-CoA to Malonyl-CoA for biosynthesis
• Insulin can allosterically activate ACC

Glycogen Synthesis Steps

• Glucose is converted to Glucose-6-phosphate, which is then converted to Glucose-1-phosphate (G-1-P)
• Phosphoglucomutase facilitates the movement of the phosphate group from the 6th position to the 1st position
• UTP is an important coenzyme in glycogen metabolism and contains 3 phosphate groups
• Inorganic pyrophosphatase removes 2 phosphate groups, providing the reaction with energy, leaving only 1 phosphate in the original triphosphate molecule.
• G-1-P combines with Uridine Monophosphate to yield UDP-Glucose
• Glycogen synthase only utilizes UDP-Glucose. The addition of G-1-P to the chain releases UDP, which is then recycled

Glycogen Synthase and Branching

• Glycogen synthase can only elongate glycogen chains that are at least 4 glucose chains long
• If present, glycogen synthase needs another molecule called "glycogenin," which initiates chain creation
• Glycogen synthase takes UDP-glucose, only the glucose end, and adds it to glycogen, forming a 1,4 alpha glycosidic bond. UDP is the byproduct
• Branching enzyme cuts off glucose chains of around 6-8 residues in length within the same chain, it connects them using an alpha 1,6 glycosidic bond, creating branches
• Glycogen synthase then adds more glycogen to the chain and fills the previous chain that was added as the branch

Glycogen Breakdown

• Glycogen breakdown occurs during fasting or exercise
• The two hormones involved in the breakdown of glycogen are epinephrine and glucagon, both of which use cAMP to activate Protein Kinase and Phosphorylases
• Epinephrine is more potent and overrides glucagon function because it acts as both a neurotransmitter and a hormone, and is made in the adrenal medulla
• Glucagon is an antagonist of insulin, made in the pancreatic alpha cells
• During fasting, glucagon promotes glycogenolysis
• Glucagon initiates a cascade using cAMP, activating protein kinase A, which activates glycogen phosphorylase Kinase but inhibits glycogen synthase
• "Phosphorylase" indicates the breakdown of glycogen
• Some health conditions result in lower phosphorylase enzyme activity, which prevents the release of a lot of glucose, leading to weakness and sickness

Glycogen Breakdown Mechanism

• The goal of glycogen breakdown is to release glucose, not form glycogen
• Phosphorylase removes glucose from the nonreducing ends of the glycogen molecule
• The reaction yields glucose-1-phosphate (G1P).
• Glycogen breakdown begins at the branches
• n-glycogen + Pi yields n-1 glycogen + G1P
• The inorganic phosphate is mediated by PLP (a cofactor)
• Glycogen phosphorylase cleaves off 1 glucose using acid-base catalysis and inorganic phosphate, which is mediated by PLP
• Phosphorylases use inorganic phosphate while phosphatases produce it ex: glc-6P -> Glucose + Pi via glucose-6-phosphatase
• It continues until there are 4 glucose molecules remaining on the branch
• Debranching enzyme removes 3 out of 4 glucose, and adds it to the linear end
• The same debranching enzyme goes back to the remaining glucose that is connected by 1,6 alpha glycosidic bond and releases it as free glucose
• G-1-P can be converted to G-6-P by phosphoglucomutase
• G-6-P can be converted to Glucose via glc-6-phosphatase

Glycogen Storage Disease (GSD) or Glycogenosis

• There are several different pathologies associated with inborn errors of metabolism
• Mutations can lead to critical dysfunction of metabolic steps
• Homozygous mutations can result in enlarged livers, low blood glucose, and low muscle strength

Lipids

• Lipids are an alternative to glycogen for energy storage
• Lipids are another class of macromolecules found within the body that are important pathways for the midterm
• This includes ketone body formation and fatty acid synthesis, which makes fatty acids from precursors in the cytosol
• Insulin signals for fatty acid synthesis. Large amounts of carbohydrates lead to large amounts of acetyl-coA, which then results in fatty acid synthesis
• Insulin activates Acetyl-coA carboxylase, the rate-limiting step of Fatty Acid Biosynthesis
• Beta oxidation, fatty acid breakdown that breaks down fatty acids for energy, occurs in the mitochondria

Glucagon and Fatty Acids

• Glucagon signals for fatty acid breakdown. It utilizes cAMP to activate lipases, which leads to fatty acid mobilization/beta oxidation that release energy
• Excess Acetyl-coA indicates the body undergoes beta-oxidation due to a lack of carbohydrates, which then signals for glucogenesis by activating pyruvate carboxylase
• Fatty acid synthesis and Beta oxidation assume an even number of carbons; odd numbers of fatty acids undergo the propionate pathway, which utilizes Propionyl coA.

Lipid Introduction

• Density comes from the high amounts of reduced state carbons compared to carbohydrates
• In Humans they are stored as Triglycerides, and in adipose cells (adipocytes)
• Mobilization consists of hydrolitic enzymes to go into adipocyte
• When low on glucose/energy, glucagon is activated, and will activate cAMP to signals for expression of Lipases that break down store energy (TAGS)
• Lipases separate Fatty Acids from the glycerol heads that are then tranferred to the blood
• Albumin binds to these fatty acids and transports them wherever they need to go

Lipases

• Lipases separate fatty acids from glycerol during complex lipid digestion
• Different lipases have different preferences for positions on glycerol backbones or to long-chain and polyunsaturated lipids
• Fatty acids are cleaved off from membrane lipids or fats

Neutral Lipids & Polar (Membrane) Lipids

• Saturated Fatty Acids: characterized by no double bonds or the potential to stack
• Unsaturated Fatty acids: Have double bonds, in the form of "oils"
• Important for membrane fluidity and inflammation
• Phospholipase works to get fatty acids from polar lipids through hydrolysis

Lipids and energy

• Lipids are essential for energy storage and for membrane formation in phospholipids.
• Adipose tissue stores lipids as Triacylglycerols to store up energy (TAGS)
• Pancreatic lipases are used to mobilize neutral lipids in the adipocyte cells called triacylglycerides
• The release of free faty acids involves using “phospholipids” Phospholipases
• Transport VLDL (very low concentration lipoproteins) to adipose tissue and muscle cells to have them either used of get stored.

Ketone Bodies

• Brain requires Glucose and Ketone bodies for energy
• They act as transportation for glucose only if conditions can permit.
• Ketone bodies helps reduce the requirement of acetyl-COA
• Adipocytes do not use ketone bodies.
• Large amount of diabetes (glucose not getting to cells) causes production to Acetyl.CA

Ketone Body Synthesis (cont.)

• In conditions of fat breakdown this happens to start large amounts of lipd metabolism.
• Under conditions of low glucose conditions the body will start to break down the fat in order to start producing Ketoaid.

Acetyl-COA

• Acryl is the first molecule that is used to make the start of the TCA cycle (mentioned in the previous text)
• It supports metabolism such as catalyzing fat, supporting synthesis of fat + the inhibition
• When acetyl is not there to regulate lipid metabolism, high volume of ketone is caused with a high volume of of ACC
• When cell activity is slow then it is because there is little presence of coA that can not be transferred to glucose.

Ketone Body Formation

• Two Acetyl CoA combine and a thioester (CoASH) is released. This is a step of releasing to make this process doable with a Thiolase.
• With an input then to create a HMG-CoA there has to be help form the enzyme called the HMG-coA HMA has two routes. HMG needs to go through reductase, and reduction with a help in the steps for cholesterol synthesis.
• lyase used the produce acetoacetate, for the process that is used to removed (co2). acetoacetate can go through oxidation then reductaiton to help with β-hydroxybutyrate.

3 Main Steps Of Formation

• The steps of Hydroxy is the main body the process of oxidation in the molecule.
• If oxidation or deconstruct is need that means there is a low or the process can not take a molecule that is made
• 4 Step to that process in need to the oxidation so that it goes into two stages.

Bodies in Check

• Bodies stay in check due in to it keeping homeostasis. When under conditions of the body starts to run out of of fat stores that may cause breaking down muscles for fuel. As such is not longer the the state of the bodies in full support

Fatty Chain Acid

• The reaction of PDC in the Mitochondria and not get transferred to ( ATP transpoters)
• In order for reaction to happen there has to be at least of atp

TCA Cycle

• A series of first reaction to bring the coA with oxalotate in to citrate from synthase
• And have both conditions on favorable side in the cycle it doesn’t pull toward high cofactors. We push to cytosol with the TCA/citrate.
• Where citrate turns onto two and gets sent Acetyl caA and Oxaloacetate.

ACC (Acetyl coA Carboxylase)

• ACC molecules carry high lipids and are needed to make sure it is not keto.
• This a multi-unit that is needed to keep everything balance such the use of (a) (b) (c) to run the chain for function

Lipid Biosynthesis

• With some coA in it helps go to the ACC where the molecule has to be made malonyl for a high energy reaction
• Where a some steps have some drop of C01 as such to not have some issues with the condensation.
• The coA go to reaction such the one (see B-Ketoacyl-ACP that it goes to that will allow us to make (NADPH) to keep the the ketone low

Keto Acid

• In the reaction there is dehydratase with can help us cleave what is not being asked of the molecule and to also give some more support.

Biosynthis

• It helps that there are additional processes to support where additional of coA is not a factor for such.
• In the process when there is 16 carbon chain this is to help thioesterase where hydrolosis can happen to keep everything afloat.

Thioesterase and Thiolase

• Two separate factor for keeping synthesis high with some reversible
• It either breaksdown or creates some the chains for Acetoacetyl CoA

Fatty Chain Synthesis

• When there is ATP being used to make long synth and with some addition of some factors the chains will react.
• And with the cycle running over and over again there isn't a need to use this is mainly due to the extra factor from one some of synth.

Unsaturated chains/ Acid & Folate

• Most the time when chains or acid have additional help this means there has to be an out from a chain that can cause more issue (the creation of something longer happens with ER.)
• Folates donate methyl group to Homocysteine, and can produce Methionine