Adenosine 5-triphosphate (ATP)

Metabolic Pathways
Metabolism: the sum total of all reactions that take place in a

living cell or organism Metabolic pathway: sequence of enzymatic reactions in which the product of one reaction is the substrate for the next

Metabolism
Metabolism is generally divided into 2 parts:
Catabolism: larger compounds are broken into smaller

compounds; this process usually generates energy (ATP is generated) Anabolism: larger compounds are synthesized from smaller ones; this process usually requires energy (ATP is hydrolyzed)
Compounds that are used, directly or indirectly, to release

energy (also called activated carrier molecules) are central to metabolism and include: ATP, GTP, NAD+, NADP+, FAD, acetyl-CoA

Metabolism: the Usual Suspects

Metabolism: the Usual Suspects II

The Eukaryotic Cell

Catabolism
Most catabolic pathways occur in a sausage-shaped

organelle enclosed by 2 separate membranes called the mitochondrion: citric acid cycle, electron transport chain, fatty acid oxidation, amino acid catabolism, oxidative phosphorylation Only glycolysis takes place in the cytoplasm of the cell

Metabolism: an Overview

Catabolism I: Digestion
When food is ingested the first stage of catabolism is to

digest it, or to break the large biopolymers into their respective monomer units
This occurs primarily in the stomach and intestines

through both hydrolytic and enzymatic processes

Glycolysis
Glycolysis is the linear cycle that catabolizes glucose (via

starch); this occurs in the cytoplasm of the cell Ultimately, 1 molecule of glucose will produce 2 ATP, 2 NADH, and 2 molecules of pyruvate after 10 steps

Glucose + 2 NAD+ + 2 ADP + 2 Pi

2 pyruvate + 2 NADH + 2 ATP + energy

G and Coupled Reactions

Recall for a reaction to be spontaneous G< 0
Coupled reactions: nonspontaneous reactions (G>0) can

be made to occur if coupled with a spontaneous reaction so that the total G (both steps) < 0 Fructose 6-phosphate + Pi fructose 1,6-bisphosphate + H2O G= 3.9 kcal ATP + H2O ADP + Pi G= -7.3 kcal

Is the conversion of F-6-P into F-1,6-bP spontaneous or nonspontaneous in absence of ATP? Write the net coupled reaction and calculate the net G for the overall reaction.

Control of Glycolysis
Due to the constantly changing energy conditions of inside

the cell, metabolic pathways must be tightly regulated: allosteric control (milliseconds) or transcriptional control (hours) Glycolysis is controlled at steps 1, 3, and 10 with step 3 being most important Phosphofructokinase is an allosteric enzyme:
Negative effectors: ATP and citrate
Positive effectors: ADP and AMP

Multiple Paths for Pyruvate I

In yeast, pyruvate undergoes alcoholic fermentation is first

split into acetaldehyde and CO2, followed by the reduction of acetaldehyde to ethanol The reduction of acetaldehyde occurs with concomitant oxidation of NADH to produce NAD+ to go back into glycolysis

Multiple Paths for Pyruvate II

In humans, when oxygen is deficient (anaerobic

conditions) like during strenuous exercise, pyruvate is converted into lactate This reduction also occurs with concomitant NADH oxidation to produce NAD+ that can continue glycolysis Build up of lactate/lactic acid results in muscle soreness

Multiple Paths for Pyruvate III

In humans, when oxygen is sufficient (aerobic conditions)

pyruvate is converted into acetyl-CoA, ready for the first step in the CAC This occurs in the mitochondria where CAC will begin

Gluconeogenesis
Gluconeogenesis: a linear anabolic pathway in which

glucose is synthesized from noncarbohydrate sources i.e. glycerol, lactate, and amino acids This cycle goes into effect during periods of fasting or early starvation when diet glucose and glycogen have been depleted This cycle is necessary for the protection of brain cells whose sole source of energy is glucose This cycle converts small non-carbohydrate molecules into glucose in a cycle resembling the reverse of glycolysis

Occurs primarily in the liver and to some extent in the kidneys

Glycogen Metabolism
Glycogen is a highly branched homopolymer of glucose

[(14) and (16)] that is an immediately available form of glucose between meals and during activity The main glycogen stores are in the liver and skeletal muscle

Glycogenolysis

Glycogenesis

Glycogenolysis Reaction

n residues

Glycogenesis Reaction

Covalent Modification
Many enzymes including those involved in glycogen

metabolism are controlled through reversible phosphorylation Glycogen synthesis is closely coordinated with its degradation, thus when glycogen phosphorylase is on, glycogen synthase is off and vice versa

Phosphorylase b (usually inactive)

phosphorylase a (active)

Citric Acid Cycle

Glycolysis yields 2 ATP, 2 NADH, and 2 pyruvate
Pyruvate can be converted into acetyl-CoA and be further

catabolized by the Citric Acid Cycle CAC is a circular cycle that takes place in the mitochondria and yields: 3 NADH, 1 FADH2, and 1 GTP Net Reaction: Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi 2CO2 + CoA + 3 NADH + FADH2 + GTP G= -11 kcal

From 1 Glucose

For a total of: 4 ATP, 10 NADH, 2 FADH2

Electron Transport Chain and Oxidative Phosphorylation: Aerobic Respiration

The ETC is a group of proteins embedded in the inner

mitochondrial membrane ETC/OP use the electrons from NADH and FADH2 to ultimately generate the majority of the ATP in an organism On Average: 1 NADH= 2.5 ATP 1 FADH2= 1.5 ATP

Shuttle Systems
The 2 NADH generated

by glycolysis in the cytoplasm cannot enter ETC directly b/c they cannot cross the inner mitochondrial Membrane They must enter indirectly through 1 of 2 shuttle systems

ATP Yield From 1 Molecule of Glucose

Lipid Metabolism
Triglycerides are concentrated stores of metabolic energy

When hydrolyzed, triglycerides form 3 fatty acids and 1

molecule of glycerol

glycerol

Dihydroyacetone

glycolysis

Fatty Acid Catabolism

-oxidation A Spiral Cycle

Each turn of the cycle produces: 1 NADH, 1 FADH2, and acetyl-CoA

Problem
1. 2. Beginning with hexanoic acid, how many passes through the oxidation spiral will take place? From your answer to part a, what is the net change in NADH, FADH2, acetyl-CoA, and ATP, when only activation and the passes through the oxidation spiral are considered? From the answer to the previous questions, what will be the total yield of ATP once all of the acetyl-CoA has moved through the citric acid cycle and all of the reduced coenzymes produced (including those from the citric acid cycle) have been used for electron transport and oxidative phosphorylation? How does the total yield of ATP obtainable from one hexanoic acid molecule compare with that from one glucose molecule?

3.

4.

Ketone Bodies
During fasting or uncontrolled diabetes, acetyl-CoA builds

up b/c there is limited oxaloacetate for it to condense with in the step 1 of the citric acid cycle (oxaloacetate will be used in gluconeogenesis to synthesize glucose) Excess acetyl-CoA is therefore used to generate 3 compounds known as ketone bodies: acetoacetate, 3hydroxybutyrate, and acetone Acetoacetate is a major fuel source in some cells (heart and renal cortex) and under starvation conditions, brain cells derive 75% of their energy from it

CongratulationsThe End!