Biochemistry Energy Storage

Anabolism

The metabolic process that builds larger molecules from smaller units, typically requiring energy input. (ATP → ADP)

Catabolism

The metabolic process that breaks down larger molecules into smaller units, releasing energy in the form of ATP. (ADP + P → ATP)

Large, complex molecules

Carbohydrates, Lipids, Nucleotides, Amino Acids

Small, simple molecules

Pyruvate, Acetyl-CoA, Glycolytic Intermediates

Energy-rich molecules

Fats, Carbohydrates, Proteins

Energy-depleted molecules

CO2, H2O, NH3

Hormones

Small molecules or proteins that connect all the organs in the body, carrying information and signals between the central nervous system adn all of the tissues.

Principles of Signal Transduction

Signal → Reception → Transduction → Response(s)

Do hormones enter the cell when initating singaling cascades?

No, they bind to the receptor on the cell surgace (in most cases)

Glucagon

released from pancreas when blood glucose is low (fasting state). Binds receptors on liver and fat cells.

Epinephrine

released from adrenal glands during activing (exercise or stress). Binds receptors on liver, fat, and muscle cells

Insulin

released from pancreas when blood glucose is high (fed state). Binds receptors on fat, liver, and muscle cells.

Leptin

released from fat cells after a meal, binds receptors in the brain which signals to stop eating, suppress appetite.

Fed State

Body decreases high levels of glucose in the blood by transporting it into cells — glucose can be used to produce ATP — excess glucose is converted into other biomolecules, such as carbohydrates, lipid, protein, metabolites, and nucleotides

Glyconeogenesis

Storage form of glucose in liver/muscle

Glycolysis

Production of energy (multiple tissues)

Fatty acid synthesis

Produce fatty acids (store as fate or use in membranes — phospholipids), Liver/Adipose

Cholesterol Synthesis

Produce cholesterol (use in membranes, hormones, bile salts), Liver

Pentose Phosphate Pathway (PPP)

Produce NADPH, intermediates for other pathways, such as nucleotides synthesis

Fasting State

Body releases or produces stored forms of fuel molecules which can be used by tissues throughout the body

Glycogenolysis (glycogen breakdown)

Increase levels of glucose in the blood (liver)

Gluconeogenesis

Increase levels of glucose in the blood (liver)

Lipolysis (fat mobilization)

Release fatty acids (liver/adipose) and glycerol release

Ketogenesis

Produce ketone bodies (liver)

Carbohydrates

Aldehydes or ketones with at least two hydroxyl groups, or substances that yield such compounds on hydrolysis (empirical formula (CH2O)n)

Monosaccharides

Simple sugars, consist of a polyhydroxy aldehyde or ketone unit

Disaccharides

Two monosaccharide units joined together by glycosidic bonds

Oligosaccharides

Short chains of monosaccharide units, or residues, joined by glycosidic bonds (<10 monosacchire units)

Polysaccharides

Sugar polymers with 10+ monosaccharide units

Anomeric Carbon

The carbonyl carbon atom

α form

Means that the hydroxyl at C-1 is below the plane of the ring

β form

Means the hydroxyl C-1 is above the plane of the ring

Glycosidic Bonds

Covalent linkage joining two monosaccharides

O-glycosidic bond

Formed when a hydroxyl group of one sugar molecule reacts with the anomeric carbon of the other

N-glycosidic bond

Formed between the anomeric carbon atom and an amine

Glycogen

The storage form of glucose in animal

Glucose units in Glycogen are…

lined by α-1, 4-glycosidic bonds, with branches formed by α-1, 6-glycosidic bonds every 10-12 glucose units

Amylose

The storage form of glucose in plants

Glucose units in Amylose are…

linked by α-1, 4-glycosidic bonds and as amylopectin, a branched polymer, with an α-1, 6-glycosidic bond for every 30 α-1,4-glycosidic bonds

Glycogen Structure

α linkages of starch and glycogen form compact hollow cylinders

Cellulose

• Component of plant cells (water insoluble)

• is a homopolymer of glucose units linked by α-1,4-glycosidic bonds

• β linkage yields a straight chain capable of interacting with other molecules to form strong fibrils

• Animals do not have the enzymes to hydrolyze β1→4 bonds

Reducing Sugar

Sugars that react with oxidizing agents

Non-reducing Sugars

Sugars that do not react with oxidizing agents

Reducing End

In disaccharides or polysaccharides, the end of a chain with a free anomeric carbon (NOT involved in a glycosidic bond)

Sucrose

Composed of glucose joined to fructose by an α-1, β-2-glycosidic linkage. It is a reducing sugar.

Lactose

Composed of a molecule of galactose joined to a molecule of glucose by β-1,4-glycosidic linkage. It is a reducing sugar.

Maltose

Composed of two glucose molecules joined by an α-1,4-glycosidic linkage. It is a reducing sugar.

Glycogen breakdown in the liver

Replenish blood glucose levels

Glycogen breakdown in the muscle

Muscle glycogen stores are mobilzed to provide energy for muscle contraction (NOT released in response to low blood glucose levels)

First step of glycogenolysis

Release glucose 1-phosphate (G 1-P) from glycogen from glycogen phosphorylase

Phosphorylatic cleavage at the nonreducing ends of glycogen chains

Advantage: energy is saved for cells from the use of phosphate from the α-1,4 bond instead of a triphosphate — done many times

Second step of glycogenolysis

Transfers braches onto main chains

Third step of glycogenolysis

Releases the residue at the (α1→ 6) branch as free glucose

(Glucose 6-Phosphate) Monomers of glucose are released from glycogen granules by a phosphorolysis reaction that creates phosphorylated glucose molecules that can (liver):

The phosphate can be removed, allowing free glucose to be transported out of the cell to replenish levels of circulating blood glucose, that can be used in the brain and other tissues when dietary glucose is not sufficient.

(Glucose 6-Phosphate) Monomers of glucose are released from glycogen granules by a phosphorolysis reaction that creates phosphorylated glucose molecules that can (muscle):

Enter glycolysis to supply energy (ATP) to cells.

Glucagon signalling results

glycogen breakdown in cells

Glucagon binds receptor…

initiating signaling cascade to activate PKA which is required to activate glycogen breakdown in liver cells

(7tm) or heptahelical receptors

Span the membrane seven times interact with heterotrimeric G proteins

Heterotrimeric G proteins or Guanine nucleotide-binding protein

Conserved family of signaling proteins with three subunits: α, β, γ

What is the subunit is the binding site for GDP or GTP

α subunit

cAMP stimulates…

Protein Kinase A (PKA) activity

Kinases

Modify substrates by phosphoryl group transfer from a nucleoside triphosphate such as ATP to an acceptor molecule

Typically, proteins are phosphorylated on the…

hydroxyl groups of Serine (Ser), Threonine (Thr), or Tyrosine (Tyr)

Phosphorylase

Catalyzes a phosphorylysis reaction — the phosphate is the attacking species and becomes covalently attached at the point of bond breakage.

Activation of glycogen phosphorylase…

starts glycogen breakdown through structural changes that make it active

Glucagon signaling pathway shut down (1)

Recepter interaction is reversible

Glucagon signaling pathway shut down (2)

Gα has inherent GTPase activity that cleaves the bound GTP to GDP

Glucagon signaling pathway shut down (3)

cAMP phosphodiesterase converts cAMP to AMP which stops activation of PKA

If liver cells (hepatocytes) are replenishing blood glucose levels, which ‘fuel’ molecule will liver cells primarily use to generate ATP?

Fatty acids derived from triacylglycerols (TAG) in fat cells (adipocytes)

Epinephrine

Hormone released from adrenal glands that bind to receptors found on liver, fat, muscle cells

Epinephrine Release

Signals to breakdown glycogen in the muscle and liver breakdown triacylglycerols in fat cells.

Fasting - Glucagon (fat cells)

activates PKA → lipolysis → TAG (1 glycerol + 3 fatty acids)

Fasting - Glucagon (liver cells)

activates PKA → glycogenolysis → glycogen (n) + glucose 1-P → glucose 6-P

Epinephrine (muscle)

activates PKA → glycogenolysis → glucose-6-P -→ anaerobic (lactate)/aerobic (acetyl CoA)

What barriers prevents glycolysis from simply running in reverse to synthesis glucose?

The reverse of glycolysis is highly endergonic under cellular conditions.

Gluconeogenesis =

Pathway that converts pyruvate and related three and four-carbon compounds to glucose

Gluconeogensis occurs in…

Animals, Plants, Fungi, and Microorganisms

Lactate

is produced by muscle during anaerobic respiration

Every amino acid can be glucogenic EXCEPT

Leucine and Lysine

Glucogenic Intermediates

Converted from the carbon skeletons of some amino acids

Glycerol

can serve as starting material for gluconeogenesis

Starting materials for gluconeogenesis

Lactate, Glucogenic amino acids, Glycerol

Bypass Reactions

Refers to the bypass of irreversible glycolytic reactions

How are the three irreversible steps in glycolysis bypasses in gluconeogenesis?

By using energy

How is this energetic barrier overcome in gluconeogenesis?

The expenditure of six NTP molecules renders gluconeogenesis exergonic

What two steps does the conversion of pyruvate into phosphoenolpyruvate (PEP) take?

carboxylase and carboxykinase

Bypass 1a:

Pyruvate to Oxaloacetate (inside mitochondria)

Oxaloacetate is shuttled into the cytoplasm as

malate

T/F: The mitochondrial membrane does not have an oxaloacetate transporter

True

T/F: reaction of oxaloacetate to malate is not readily reversible under physiological conditions

False

How does malate leave the mitochondrion?

Through a malate transporter in the inner mitochondrial membrane

Oxidation of malate to oxaloacetate forms what?

NADH in the cytoplasm

Bypass 1b:

Oxaloacetate is converted to PEP

Bypass 2:

Fructose 1,6-bP → Fructose 6-P

Bypass 3:

Glucose 6-P → Glucose

What type of reaction is taking place during the last two irreversible steps in gluconeogensis?

Hydrolysis with the removal of phosphate catalyzed by phosphatase

Key Enzymes

operate far from equilibrium and are highly regulated

Gluconeogenesis and glycolysis are reciprocally regulated

Activities of certain enzymes (at irreversible steps) within gluconeogenesis and glycolysis are regulated so that within a cell, one pathway is relatively inactive while the other is highly active

The rationale for reciprocal regulation is that

Glycolysis will predominate when glucose is abundant and Gluconeogenesis will be highly active when glucose is scarce

Fructose 2,6-biphosphate is an allosteric effector that helps regulate glucose metabolism

It stimulates glycolysis and inhibits gluconeogensis