 Macromolecules – carbohydrate, fatty acid, amino acid, nucleic acid  Bioenergetics, gluconeogenesis – glycolysis and the TCA cycle  Oxidative phosphorylation, anaerobic metabolism  Glycogen synthesis and breakdown

glycolysis Krebs cycle (TCA) Anaerobic alcohol fermentation Anaerobic respiration (pyruvate to lactate) Cori cycle Various shuttle

TCA CYCLE

glucose Fructose 1,6 biphosphate 2 pyruvate Aerobic oxidation Citric acid cycle (TCA) Oxidative phosphorylation 6CO 2 + 6H 2 O Anaerobic alcoholic fermentation Anaerobic glycolysis 2 lactate 2CO ethanol 2NAD + 2NADH 2 ATP + 2 Pi 2 ADP 2NADH 2NAD + 2NADH 2NAD + 6O 2 cytoplasm

EMP pathway for breakdown of glucose to pyruvate (glycolysis) Krebs, tricarboxylic acid (TCA), or citric acid cycle for conversion of pyruvate to CO 2 and NADH Respiratory or electron transport chain for formation of ATP by transferring electrons from NADH to an electron acceptor

 Carbohydrates – mono-, di- and polysaccharide glucose  give us energy  made up of 6 carbon rings  simple sugar  is the main rate limiting substrate in all metabolic pathways  protein ?  nucleic acid  Acid amino?

Glucose  pyruvate

   cguide/unit6/metabolism/cellresp/glycol_an.h tml cguide/unit6/metabolism/cellresp/glycol_an.h tml  a/ch06/glycolysis.swf a/ch06/glycolysis.swf  t/Life_Science/Metabolomics/Key_Resources/ Metabolic_Pathways/Glycolytic_Pathway.html

 Glycolysis is a partial breakdown of a six-carbon glucose molecule into two, three-carbon molecules of pyruvate, 2NADH+2H +, and 2 net ATP as a result of substrate-level phosphorylation.  Glycolysis occurs in the cytoplasm of the cell. The overall reaction is: glucose(6C) + 2NAD + 2ADP + 2 inorganic phosphates (Pi)  2 pyruvate (3C) + 2NADH + 2 H net ATP

2 P i Embden-Meyerhof Parnas (EMP) pathway cytoplasm

Embden-Meyerhof Parnas (EMP) pathway Occurs in cytoplasm

Glycolysis pathway

Hexokinase Glucosephosphate isomerase phosphofructokinase Triosephosphate isomerase

Glyceraldehyde 3 phosphate dehydrogenase Phosphoglycerate kinase Phosphoglycerate mutase enolase Pyruvate kinase

glucose Fructose 1,6 biphosphate 2 pyruvate Aerobic oxidation Citric acid cycle (TCA) Oxidative phosphorylation 6CO 2 + 6H 2 O Anaerobic alcoholic fermentation Anaerobic glycolysis 2 lactate 2CO ethanol 2NAD + 2NADH 2 ATP + 2 Pi 2 ADP 2NADH 2NAD + 2NADH 2NAD + 6O 2 cytoplasm

 Glycolysis is a 10-step pathway which converts glucose to 2 pyruvate molecules. The overall Glycolysis step can be written as a net equation: Glucose + 2xADP + 2xNAD+ -> 2xPyruvate + 2xATP + 2xNADH GlucoseADPNAD+PyruvateATPNADH  Glycolysis consists of two main phases. First phase, energy investment. During this step 2xATP are converted to 2xADP molecules. Second phase, energy generation. During this step 4xADP are converted to 2xATP molecules and 2xNAD+ are converted to 2xNADH moleculesATPADP ATPNAD+NADH

Anaerobic respiration (pyruvate  lactate )

LDH ANAEROBIC CONDITION NAD + GENERATION

Lactate produced in muscles by glycolysis is transported by the blood to the liver Gluconeogenesis in the liver converts the lactate back to glucose, which can be carried back to the muscles by the blood. Glucose can be stored as glycogen in the muscle until it is degraded by glycogenolysis. BLOOD VESSEL MUSCLE LIVER AEROBIC ANAEROBIC gluconeogenesis glycolysis

Cycling of glucose due to glycolysis in muscle and gluconeogenesis in liver Glycolysis in skeletal muscle produces lactate under conditions of oxygen debt such as sprint. Skeletal muscle has comparatively few mitochondria, so metabolism is largely anaerobic in this tissue. The buildup of lactate is responsible for the muscular aches that follow strenuous exercise. Gluconeogenesis recycles the lactate that is produced (lactate is first oxidized to pyruvate).

Cori Cycle

Anaerobic alcohol fermentation

Responsible for the bubbles in beer and sparkling wines ADH NAD + generation

pyruvateAcetyldehyde Ethanol

Aerobic and anaerobic glycolysis: Overview  The metabolism of glucose through aerobics or anaerobic pathways is a non-oxidative process. Both types of glycolysis release a small fraction of potential energy stored in the glucoe molecules.  During the first 10 steps of glycolysis, only a small part of all glucose energy is released and the rest of the potential energy is released during the last steps after glycolysis. For this reason aerobic degradation is much more efficient than anaerobic metabolism.  That is why the aerobic mechanism is now much more spread within living organisms, but nevertheless anaerobic pathways still take place even in animals under certain physiological circumstances.

 Both are NADH-linked dehydrogenase  Allosteric enzymes  tetramers

KREB’s cycle

TCA CYCLE

 Conversion of pyruvate to glucose  Not the exact reversed glycolysis, as some of the reactions are irreversible and is by- passed in gluconeogenesis  Example: a hiker who goes directly down a steep slope but who climbs back up the hill by an alternative, easier route.  3 main steps are by-passed (refer to the pathway……

Glycolysis

pyruvate oxaloacetate Phosphoenolpyruvate (PEP) phosphoglycerate Triose phosphateFructose 1,6 biphosphate Fructose 6-phosphate Glucose 6-phosphate glucose CO 2 + ATP Pi + ADP GTP GDP + Pi Pyruvate carboxylase PEP carboxykinase Fructose biphosphate phosphatase Glucose 6- phosphatase Phosphofructokinase in glycolysis, require ATP Hexokinase in glycolysis, require ATP 2 steps (reverse of glycolysis) Aldolase, same as glycolysis G, 6-phosphate isomerase, same as glycolysis The pathway of gluconeogenesis. The enzymes in blue are unique to this pathway. The enzymes that catalyzed reversible reactions are shared with the glycolytic pathway

Pyruvate  oxaloacetate  phosphoenolpyruvate Fructose-1,6-biphosphate  fructose-6- phosphate Glucose-6-phosphate  glucose + Pi Very important point

pyruvate oxaloacetate Phosphoenol pyruvate (PEP) CO 2 + ATP ADP + Pi H2OH2O 2H + Pyruvate carboxylase PEP carboxylase GTP GDP + CO 2 Allosteric enzyme Mg 2+ (cofactor) biotin (cofactor) – carrier for CO 2 Acetyl CoA (allosteric effector) Mg 2+ Control point/rate limiting step [acetyl CoA]  than is needed to supply the TCA cycle  gluconeogenesis Meaning that when the supply of acetyl CoA is supplus in TCA cycle, then only it moves to the gluconeogenesis pathway. If not this process is unlikely to happen.

Gluconeogenesis & Glycolysis Glycolysis Gluconeogenesis Phosphoenolpyruvate (PEP) pyruvate oxaloacetate Pyruvate kinase Pyruvate carboxylase PEP carboxy kinase

Fructose 1,6- biphosphatase

(In Glycolysis)

Bypass II…….continued Allosteric enzyme Inhibited by AMP (adenosine monophosphate) & Fructose 2,6- biphosphate Stimulated by ATP Control point (when the cell has an ample supply of ATP, the formation rather than the breakdown of glucose is favored.

gluconeogenesis glycolysis

(1) (2) (3) (4) Reaction (1) : Mitochondria Reaction (2) : Mitochondria Reaction (3) : Cytoplasm Reaction (4) : Cytoplasm

Produced during Glycolysis in 1st step Needed in Glycolysis step 6, TCA cycle, anaerobic condition

cytosol mitochondria membrane

Most efficient shuttle mechanism found in mammalian kidney, liver and heart. Make use of the fact that malate can cross the membrane while oxaloacetate do not. VIP is that the NADH in the cytosol produces NADH in the mitochondrion. Aspartate can cross the membrane, then converted to oxalacetate in the cytosol, completing the cycle of the reactions. The NADH that is produced in the mitochondrion thus passes electrons to the elctron transport chain. With the malate-aspartate shuttle, 3 molecules of ATP are produced for each molecule of cytosolic NADH rather than 2 molecules of ATP in the glycerol phosphate shuttle, which uses FADH 2 as a carrier.

Glycerol phosphate Dihydroxyacetone phosphate FAD FADH 2 ATP Mitochondrial glycerol phosphate dehydrogenase mitochondria Glycerol phosphate Dihydroxyacetone phosphate NADH + H + NAD + CYTOSOL GLYCOLYSIS Cytosol glycerol phosphate dehydrogenase membrane

NADH is produced by glycolysis, which occurs in the cytosol, but NADH in the cytosol cannot cross the mitochondrial membrane to enter the electron transport chain. However the electrons can be transferred to a carrier that can cross the membrane. The number of ATP molecules generated depends on the nature of the carrier, which varies according to the type of cell in which it occurs. One carrier that has been extensively studied is Glycerol phosphate shuttle in insect flight muscle. Glycerol phosphate and dihydroxyacetone can cross over the membrane. Oxidising agent is FAD and the product is FADH 2, which then passes electrons through the electron transport chain, leading to the production of 2 molecules of ATP for each molecule of cytosolic NADH. This mechanism has also been observed in muscle and membrane.