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DENF 1521 Biochemistry

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Introduction to Metabolism

Instructions
  1. Please enter your name below to be sure you get credit (before doing anything else).
  2. Then study Lesson 1 at your own pace. When Practice Exercises appear, click the appropriate button to choose your answer. Then press the "Get Feedback..." button to find out how you did. Continue to try again if you miss.
  3. After studying Lesson 1, and responding to all practice exercises, follow instructions at the end to submit your responses for Lesson 1 participation credit.
NAME:
Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism

Lesson 1
Introduction to Metabolism

1A Lesson objectives

The objectives of this lesson are to understand:

  1. Basic thermodynamic principles as they relate to metabolism
  2. The importance of ATP as the energy "currency"
  3. That the major electron carriers in the cell are NAD+ and FAD
  4. That coenzyme A is the carrier of acyl groups
  5. The role of vitamins in metabolism
  6. The 3 stages that contribute to the overall strategy of metabolism

1B Brief review of thermodynamics

The most useful thermodynamic concept relavant to biochemistry is that of free energy. The change in free energy is defined as (delta G zero). If the <0 for a reaction, then that reaction is thermodynamically favorable. The term refers to the standard change in free energy for specific set of conditions. ' (pronounced delta G zero prime) refers to the standard change in free energy for specific set of conditions. In biological systems this is a measure of the free energy change at pH = 7.0.

An important concept to remember is that thermodynamically unfavorable reactions can be driven by coupling this reaction to a favorable one. This is a very important fact to remember when studying metabolism.

For a reaction in which A C + D via the intermediate B the following reactions can be written:

reaction 1 A B + C +4 kcal/mol
reaction 2 B D -9 kcal/mol
sum of 1 & 2 A C + D -5 kcal/mol

The reaction of A going directly to B + C would not occur spontaneously because of the positive = +4 kcal/mol. Coupling this reaction with the reaction of B going to D which has a negative = -9 kcal/mol, gives an overall = -5 kcal/mol. This combined reaction is thermodynamically favorable. Reactions with a positive are often coupled to the hydrolysis of ATP which has a = -7.3 kcal/mol.

Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism
Introduction to metabolism
Practice
Exercise 1:

A thermodynamically unfavorable reaction can be made favorable by

No Response
Coupling it to a reaction with a positive delta G
Coupling it to a reaction with a negative delta G
Adding an enzyme
Coupling it to the hydrolysis of water
Practice
Exercise 2:

A reaction which has a negative is a thermodynamically favorable reaction.

No Response
True
False
Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism

1C Adenosine Triphosphate (ATP)

ATP is considered the "currency" of free energy in living organisms. ATP is a nucleotide consisting of an adenine, a ribose, and a triphosphate unit. ATP is an energy-rich compound because it contains 2 phosphoanhydride bonds. ATP can be hydrolyzed to either ADP or AMP as shown in the reactions below. Each reaction has a = -7.3 kcal/mol. The enzyme adenylate kinase can interconvert ATP, ADP and AMP.

The hydrolysis of ATP

ATP + H2O ADP + Pi + H+
ATP + H2O AMP + PPi + H+

Some metabolic reactions utilize analogues of ATP, namely GTP, UTP, or CTP, as sources of energy. There are enzymes which can catalyze the transfer of the terminal phosphate from one nucleotide to another. Examples of such transfers are:

ATP + GDP ADP + GTP
ATP + CMP ADP + CDP

Another important question relates to the utilization of ATP. ATP is not used as the long-term storage of energy in the cell. ATP serves as an immediate donor of free energy for biological reactions in the cell. Therefore, the turnover of ATP is very high. In a resting human, 40kg of ATP is utilized in a 24 hour period. The structure of ATP allows it to function efficiently in phosphoryl group transfer reactions. A combination of electrostatic repulsion and resonance stabilization are involved. ATP has 4 negative charges and because they are close together there is a great deal of repulsion. This repulsion is reduced when ATP is hydrolyzed. ATP is often referred to as a high energy phosphate compound because large amounts of free energy are released upon hydrolysis of these phosphoryl bonds. Another way of diagrammatically representing this high energy phosphate bond is ~P.

1D Creatine phosphate

Creatine phosphate, also known as phosphocreatine, serves as a reservoir of high energy phosphate in muscle.

The ATP in muscle only lasts for about 1 second. Therefore, another source of high energy phosphoryl groups is needed to sustain muscle activity for longer periods of time. Creatine phosphate serves this function because the ' for forming ATP as shown in the reaction below is -3 kcal/mol. The phosphoryl group is transferred to ADP to form ATP.

Creatine phosphate + ADP + H+ ATP + creatine
The amount of creatine and creatine phosphate in the muscle is approximately 10 times the amount of ATP present. The high amount of creatine phosphate allows the muscle to maintain high ATP levels during strenuous exercise. Creatine phosphate serves as the chief source of energy for a sprinter during the first 4 seconds of running.
Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism
ATP
Practice
Exercise 3:

ATP contains how many phosphoanhydride bonds?

No Response
One
Two
Three
None
Practice
Exercise 4:

ATP serves as an immediate donor of free energy for biological reactions.

No Response
True
False
Practice
Exercise 5:

The enzyme adenylate kinase catalyzes the interconversion of

No Response
GTP and GMP
Creatine phosphate and ATP
ATP and AMP
Glucose and glucose 6-phosphate
Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism

 

1E Major electron carriers used in the oxidation of fuel molecules

In the process of the breakdown of metabolic fuels electrons are ultimately passed to O2. However, this transfer does not occur directly. Special carriers, which are either pyridine nucleotides or flavins are used. These carriers pass their electrons through a series of carriers in the mitochondrial membrane to O2 in a process called oxidative phosphorylation.

The major acceptor of electrons in the cell is nicotinamide adenine dinucleotide abbreviated NAD+ (see structure below). The nicotinamide ring of NAD+ accepts a hydrogen ion and 2 electrons (equivalent to a hydride ion) forming the reduced form NADH.

Flavin adenine dinucleotide (FAD) is another carrier molecule used in the oxidation of fuel molecules. FAD can accept 2 electrons (as does NAD+) to form the reduced form of the carrier, FADH2. FAD takes up a proton as well as a hydride ion, in contrast to NAD+ which takes up hydride only.

The reduced and oxidized forms of NAD+ and FAD

The reactive site indicates the point at which electrons are added to form the
oxidized form of the carrier, either NADH or FADH2

NAD+

FAD
NAD FAD

 

1F Coenzyme A is the carrier of acyl groups

Another molecule which is important to metabolism is coenzyme A (CoA). This molecule is composed of adenosine 3',5'-bisphosphate and phosphopantetheine. The reactive group in this molecule is a sulfhydryl group. Acyl groups form a thioester bond with coenzyme A forming acetyl-CoA. Acetyl-CoA carries activated acetyl groups in a manner similar to the activated phosphate groups carried by ATP. The hydrolysis of acetyl CoA to acetate and Coenzyme A has a large negative . Therefore, this is a high energy bond.

 

The structure of Coenzyme A
coenzymeA
The adenosine 3',5'-bisphosphate part of the molecule is shown in blue and pantothenic acid in green. The red arrow indicates the reactive sulfhydryl which forms a thioester with acetyl groups.
Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism
Carrier molecules
Practice
Exercise 6:

NAD+ is a major acceptor of electron in metabolic reactions in the cell.

No Response
True
False
Practice
Exercise 7:

The major carrier of acetyl groups in the cell is

No Response
NAD+
Coenzyme A
NADPH
O2
Practice
Exercise 8:

Electrons derived from the breakdown of fuel molecules ultimately are passed to

No Response
Coenzyme A
FAD
Glucose
O2
Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism

1G Vitamins

Vitamins are complex organic molecules required in the diet of higher animals. These molecules are needed in small quantities for normal metabolism The higher animals have lost the ability to synthesize these compounds. Deficiencies in many vitamins can lead to various metabolic disorders. The water soluble vitamins are those which are soluble in water or polar solvents. Their major role is as components of coenzymes as indicated in the table below. The other group of vitamins, the fat-soluble vitamins, serve a variety of functions including being involved in blood clotting and vision. More information on the vitamins including their 3-dimensional structures can be found be clicking here.

Water soluble vitamins
Vitamin
Dietary precursor 		Coenzyme derivative Chemical group transferred Example
Thiamin
(Vitamin B1) 		Thiamin pyrophosphate Aldehydes Pyruvate dehydrogenase
Riboflavin
(Vitamin B2) 		Flavin adenine dinucleotide Electrons FADH2
Nicotinate
(Niacin) 		Nicotinamide adenine dinucleotide Hydride ion NADH
Pyridoxine
(Vitamin B6) 		Pyridoxal phosphate Amino groups Transamination reactions
Pantothenate Coenzyme A Acyl groups Fatty acid degradation
Biotin Covalently attached to carboxylases CO2 Pyruvate carboxylase
Folate Tetrahydrofolate One-carbon groups Nucleotide synthesis
Cobalamine
(Vitamin B12) 		5'-deoxyadenosylcobalamine H atoms and alkyl groups Methyl malonyl CoA mutase
Vitamin C - Reducing agent (antioxidant) Procollagen proline hydroxylase
Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism
Vitamins
Practice
Exercise 9: 		The major biological function of the water soluble vitamins is to

No Response
Bind free glucose
Inhibit blood coagulation
Act as cofactors for enzymes
Carry electrons


Practice
Exercise 10:

The cofactor involved in carrying activated carbon dioxide is

No Response
Biotin
Folate
Pyridoxal phosphate
Cobalamin
Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism

 

1H Overall strategy of metabolism

The overall strategy for metabolism consists of breaking down complex foodstuffs to derive energy from them. Stage I involves digestion, breaking down macromolecules to smaller units such as fatty acids, glucose, or amino acids. Stage II involves conversion of these smaller units into acetyl CoA and other simpler molecules. In stage III, acetyl CoA enters the citric acid cycle with the generated electrons (in the form of reduced coenzymes) used by oxidative phosphorylation to generate ATP as electrons are passed to O2. This third stage generates approximately 90% of the ATP formed from the degradation of foodstuffs.

It is very important for metabolic pathways to be tightly controlled. However, these controls must be flexible in order to respond to differing metabolic conditions. For example, after a meal it makes sense to store molecules such as glucose in the form of glycogen for later use. A very important point is that biosynthetic and degradative pathways are almost always distinct. Thus, the pathway and enzymes involved in the synthesis of glycogen are different from those utilized to degrade glycogen. In some cases, such as glycolysis and gluconeogenesis, only key steps will be different in the biosynthetic and degradative pathway. There are three main mechanisms which govern the control of metabolic pathways.

  1. Control the amounts of enzyme present in the cell
  2. Control the catalytic activity of the enzyme
  3. Control the accessibility of substrates

Specific examples of each of these metabolic controls will be seen in subsequent lessons.

1I Energy charge

The energy charge of the cell is a measure of the relative amounts of ATP, ADP, and AMP in the cell. It is the degree to which the system is filled with high-energy phosphate groups. If all of the nucleotide was in the form of ATP, the energy charge of the cell would be 1.0. If everything was in the form of AMP, the energy charge would be 0. Most cells have an energy charge between 0.85 and 0.95.

Energy charge = [ATP] + 1/2 [ADP]/[ATP] + [ADP] + [AMP]

Many reactions in the cell are controlled by the energy status of the cell. If the energy charge of the cell is low, then pathways which result in the production of ATP are favored. If the energy charge is high, then pathways the utilize ATP are favored. For example, glycolysis (breakdown of glucose) is favored by low energy charge while gluconeogenesis (synthesis of glucose) is favored by high energy charge. The following demonstrates this graphically.

Effect of energy charge on metabolic pathways

Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism
Overall strategy of metabolism
Practice
Exercise 11:

The final stage in the extraction of energy from food involves the generation of ATP.

No Response
True
False
Practice
Exercise 12:

The first stage in the breakdown of fuel molecules is

No Response
Generation of ATP by oxidative phosphorylation
Formation of acetyl CoA
Breakdown of macromolecules to smaller units
Formation of glucose 6-phosphate
Practice
Exercise 13:

Metabolic pathways which generate ATP are favored if the cell's energy charge is low.

No Response
True
False
Practice
Exercise 14:

Only metabolic pathways in the cytoplasm are regulated by the cell's energy charge.

No Response
True
False
Dental Biochemistry Brush
DB Bullet Lesson 1 Introduction to Metabolism

1J Summary

After completing this lesson you should understand the following about intermediary metabolism.

  1. Metabolic reactions in the cell follow basic thermodynamic principles
  2. ATP as the energy "currency"
  3. Coupling of ATP hydrolysis to reactions with positive free energy values allows unfavorable reactions to occur in the cell
  4. NAD+ and FAD are the major electron carriers in the cell
  5. Acetyl-coenzyme A is the carrier of activated acyl groups are carried in the cell
  6. Water soluble vitamins serve as cofactors for many of the enzymes involved in metabolism
  7. The overall strategy of metabolism involves the breakdown of large macromolecules into smaller units which are then used to synthesize ATP via oxidative phosphorylation
  8. The energy charge of the cell is an important factor in the regulation of metabolic pathways

Final Instructions


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End Lesson 1
Introduction to metabolism
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