Week Five Lecture 560B on Line

8/3/2019 Week Five Lecture 560B on Line

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Week Five Lecture

Biochemistry of Nutrition

Dr. Charles Saladino

Introduction

Think of emptying your bedroom and then filling it with golf balls, so as occupy every

cubic inch of space wall to wall, floor to ceiling. Without a catalyst, it would take a

year to remove one cubic foot of those golf balls. Add a catalyst, and the room isemptied out in one second! Does that sound dramatic? I certainly think so; and that is

why I use this analogy to emphasize the importance of the class of proteins called

enzymes biological catalysts. They speed up a chemical (metabolic) reaction without

themselves being consumed in the reaction. Enzymes provide an alternate, energeticallyfavorable reaction pathway, not the same as the uncatalyzed reaction.

Slow acting enzymes only speed up reaction rates about 1000 times. Fast enzymes,

however, can increase the rate of a reaction by as much as 1011

times. Just think of thatnumber. In fact, it is absolutely safe to say that having no enzymes in the cell would be

incompatible with life. Metabolic reactions would proceed just too slowly to sustain aliving system, as almost all reactions in the body are enzyme-mediated.

The term enzyme is derived from the Greek, en, in and zyme, leaven. The term

was first coined in 1878 by Kuhne to designate a catalytically active substance,previously known as ferments. Although there are literally thousands of different

enzymes within the living cell, they can be classified into six general categories,

according to their respective functions:

1. Oxidoreductases. This class of enzymes is so named for obvious reasons.They catalyze oxidation-reduction reactions. Dehydrogensases are a prominentexample of enzymes from this group.

2. Hydrolases catalyze bond cleavage by adding a single water molecule across

the broken bond. Cleavage of a peptide bond is such an example.3. Transferases catalyze the transfer of groups contining N, C, or P, for example,

the addition of a carboxyl group during a carboxylation reaction.

4. Lyases catalyze the breaking of C-C or C-S, and some C-N. An example is a

decarboxylation reaction, where carbon dioxide is removed from an organic acid.5. Isomerases catalyze rearrangements of molecules in the formation of pairs of

optical or geometric isomers, for example. You will be more aware of this when

we discuss glycolysis.6. Ligases catalyze the formation of bonds between C-O, C-S, C-N, for example.

However, the important distinction for this class of enzymes is the energy

requirement in the form of ATP. Repairing a break in the sugar/phosphatebackbone of DNA is an example where a ligase is required.

We must now start to consider exactly what an enzyme does, how it does it, and what the

consequences of its action are. That is a lot of material to cover. Lets start with the


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simple, such as the molecule upon which the enzyme acts is called the substrate, which

you probably already know. We start with the simple notion that:

k1

k2

E (enzyme) + S (substrate) ES E + P (product)

k-1

k-2

Although we show a reversible arrow after the ES complex, it is highly unlikely that once

that complex is formed that the reaction would not proceed to completion. (When welook at energy curves later, you will see precisely why.) Note that the enzyme is

recovered after the reaction is over. Obviously, the world of biochemical reality is far

more complex than the above equation implies. I personally consider it as much

conceptual as actual, because many reactions require multiple enzymes, multiplesubstrates, and many critical cofactors, in order for the enzyme to function at all. What

value this has, however, is in understanding the kinetics - the rate of reaction over time.

Why discuss this? Is this just an academic exercise in chemistry? Or, as is decidedly thecase, does kinetics bear strongly upon enzyme function in metabolism and in the

interpretation of enzyme inhibition? This is where we are headed in this weeks lecture.

You will notice at the arrows in the above equation, that there are four rate constants.

The value of the rate constant determines which direction the reaction will take (i.e.

which direction the equilibrium favors). Again, once the ES complex is formed, thereaction will go to completion.

We now need to talk about the famous Michaelis/Menton equation, which describes how

the velocity of an enzyme-catalyzed reaction will vary as a function of the substrateconcentration. Thus:

Vo = Vmax [S] where: Vo = initial reaction velocityK

m+[S] V

max= maximum velocity

S = substrate concentrationK

m= Michaelis constant

Now a picture will be worth a thousand words to describe the above equation graphically.

The two graphs below are two different representations of Michaelis/Menton kinetics. In

the first graph we plot the velocity of the enzyme-catalyzed reaction against the substrate

concentration, assuming a small amount of enzyme present. Notice that the initialvelocity rises in a straight line, which represents the velocity or rate at which the number

of substrate molecules are converted to product per unit time (usually mol/minute).This is a first order reaction with respect to substrate, due to the approximately

proportional relationship of velocity to substrate concentration. Eventually, at highersubstrate concentrations, the reaction reaches a maximum velocity (Vmax), no matter

how much additional substrate is present. Each enzyme has its own characteristic Vmax,

which really represents the saturation with substrate of all available binding sites on the

enzymes present.

Another very useful parameter of this plot is the Km. Clearly it is the substrate


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concentration at which one half Vmax is reached. This very important substrate

concentration value assesses the affinity of the enzyme for the substrate. Now, a large

Km value means a low affinity of the enzyme for the substrate. That makes sense, if youconsider that you would need more substrate to get to half maximum velocity than you

would with a low Km, where the affinity of enzyme for substrate is greater, and thus

requiring less substrate to achieve half Vmax. Make sense? Please tell me if you arehaving any problems with this very important concept.

The second graph is called the Lineweaver/Burke plot, otherwise known as the doublereciprocal plot, 1/V vs. 1/S. Obviously, the Km is calculated from where the line

intersects the substrate axis, whereas the Vmax is calculated from where the velocity axis

is intersected. The real advantage of this plot vs. the first one is that calculating a precise

Vmax value is more accurate with a Linweaver/Burke plot, because in the first graph, it isdifficult to say exactly at what substrate concentration the Vmax is achieved. Only good

estimates can be achieved, but not as accurately as with the double reciprocal plot.

Now getting away from the theoretical for a moment, by way of practical example, lets

look at the Km values (molar) of a few enzymes. Lysozyme has a value of 6 M,whereas that of carbonic anhydrase is 8000 M. Why such a difference? The action of

lysozyme on a bacterial cell wall need not be instantaneous in molecular time. Thereaction can occur more slowly with a Km of 6 M and a maximum turnover of only 0.5

molecules of bacterial cell wall substrate (Hexa-N-acetylglucosamine) per second. In

stark contrast, the Km of carbonic anhydrase is 8000 M, with a maximum turnover rateof 600,000 molecules of carbonic acid being converted to water and carbon dioxide per

second! This is because the carbon dioxide/oxygen exchange is very rapid, and the


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enzyme is critical to that exchange, as we have previously discussed. Therefore, the

Vmax reflects the need (or lack thereof) for the speed with which the enzyme must act. It

also acts as an indirect proof that an ES complex exists, because uncatalyzed reactions donot show the saturation effect (a Vmax).

Active Site of the Enzyme

In the proteins lecture, I stressed the need for specificity of action in the case of manyclasses of proteins. The enzyme is a prime example of the need for specificity between

enzyme and substrate. Before going to the heart of enzyme specificity, lets illustrate this

principle by way of example. When we study carbohydrates, you will learn, if you dont

already know, that galactose and glucose are sterioisomers of each other, and that theyare otherwise identical, except for the direction one hydroxyl group is pointing in glucose

vs. galactose. This small difference in the angle of a small group is picked up by the

enzyme glucose kinase, which phosphorylates glucose, but will not phosphorylate

galactose. This is a prime example of how specific an enzyme can be. What accounts forthis specificity? The answer primarily is the active site of the enzyme.

The active site of an enzyme is a region that binds the substrate and a coenzyme and

possibly other cofactors. Although the substrate can bind to other regions of the enzyme

in a less specific manner, the active site is where true specificity resides. Lets look at

some properties of all active sites.1. First, the active site is a three-dimensional crevice or cleft formed by groups that join

different parts of the primary sequence of the protein. In other words, the active site

might contain amino acids # 12, 44, 67, 140, and 230, all brought together throughsecondary and tertiary levels of folding. In other words, residues far away from one

another in the primary sequence might interact more significantly than adjacent ones.

2. As state in the first point, active sites are cervices or clefts to which the substratebonds. This area is generally hydrophobic, unless water is a reactant. This non-polar

area enhances catalysis and substrate binding.

3. The active site occupies but a small part of the entire volume of the enzyme. Here is

an email assignment question: Why is there such a big enzyme with such a small

active site? There are at least two good answers.

4. A substrate will bind an enzyme by many weak interactions. These are non-covalent

bonds, such as hydrogen, hydrophobic interactions, and van der Waals forces (thesebeing so weak, that only when the substrate and enzyme are very close do they matter,

and there must be a large number of them before they become significant).

5. The enzyme and the substrate must be a complementary fit. However, this does notstart off as a lock and key, but rather becomes complementary as the enzyme and

substrate approach each other and possibly after the substrate binds. This is called the

induced fit model, which replaces the antiquated lock and key theory. This required highdegree of specificity is satisfied, in part, by the directional character of hydrogen bonds

between enzyme and substrate. In summary of this point, the high degree of specificity

of bonding between enzyme and substrate at the active site is dependent upon a precisely-

defined arrangement of atoms in the active site.


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We have been discussing the active site, as though there were always just one per

enzyme. In fact, that is not true. Many enzymes have multiple active sites. Then howcould we know that? There are several technological methods that can be used.

However, if we look at the kinetics of the enzyme, the answer can be forthcoming. You

notice that the Michaelis/Mention kinetics curve is hyperbolic, that is, the graph starts offwith a straight line portion, followed by an approach to and then the achievement of

saturation. This curve defines the kinetics of enzymes with one active site. However, if

the curve represents an enzyme with multiple subunits and active sites and/or the enzymeis controlled allosterically, the following sigmoidal curve appears:

If you remember our discussion about allosterism, one hallmark would be the changing

the shape or activity of a protein (like an enzyme) by binding an allosteric effector to it, ata place in the structure other than the active site. This type of enzyme manifests the

sigmoidal kinetics curve. If this enzyme were to be inhibited, it would likely follow a

hyperbolic shape again, but below that of the sigmoidal curve.

Enzyme Inhibition

While we are still on the topic of enzyme kinetics, lets look at two types of enzyme

inhibition, competitive and non-competitive. To understand them, you will have needed

to grasp the concept of the Km.

Below is the Michaelis/Menton kinetics curve for normal kinetics and for competitive

inhibition. A competitive inhibitor is one that ties up the active site, making it

unavailable to the substrate. Only a flood of substrate will reverse this inhibition. Noticehow in the inhibition curve, the Km is much greater, but Vmax is eventually achieved.

Do you understand why the Km is larger? The answer is because the affinity of the

enzyme for the substrate is compromised, due to the inhibitor occupying the active site ofthe enzymes. Obviously, this is a dose effect, in that the more inhibitor, the greater the

number of enzymes with an unavailable active site will be present, and the greater

amount of substrate will be needed to reverse the competitive inhibition.


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The next curve shows a non-competitive inhibition. Here the inhibitor binds the enzyme,

but not at the active site. Perhaps by allosterism or some other structural change, the

enzyme is not able to form the ES complex as well. You will notice that the Km is

affected very little, whereas Vmax can never be achieved. By comparing these twocurves, or two Lineweaver/Burk plots, one can differentiate competitive from non-

competitive inhibition. Adding more substrate here still does not allow Vmax to bereached.

Allosterism and Enzyme Regulation

Many enzymes have multiple active sites and multiple subunits. They do not follow theusual Michaelis/Menton hyperbolic curve. Rather, there shape is signmoidal (refer to the

text-see below). Their regulation then is going to be allosteric. This critically important

concept states that an enzyme (or other types of protein) can be activated or deactivatedby 3-dimensional conformation changes in the structure. This is usually brought about by

an allosteric effector(s) that bind to key domain sites. Such regulators can be a variety of

substances, including metals, phosphates, cAMP, etc. If the enzymes in activated by

such binding, then the ligand doing the binding is sais to be a positive allosteric effector.If the ligand deactivates the enzyme, then it is a negative allosteric effector. In either

case, the enzymes activity is changed due to a conformational change brought about by

the binding of the respective effector. (We will see some good examples of this when we


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study glycogen formation and breakdown by the highly-regulated glycogen synthase and

glycogen phosphorylase enzymes, respectively.) Such regulations are very common in

the living cell. Remember, what we are dealing with here is not more or less enzyme, butrather an enzyme that is active or inactive, due to the 3-dimensionality of the structure

that the enzyme acquires. For more clarification on allosteric regulation of enzymes,

read Section 10.10 in Devlin and learn that material well for the next exam.

In addition to the ways of controlling metabolism through regulation of enzymes, two

more items can be added. First, enzymes can be up-regulated or down-regulated. Thissimply means synthesizing more or less enzyme, respectively. The second issue is

feedback regulation, otherwise known as end product inhibition. What this means is the

end product of a metabolic pathway regulates the rate of its own synthesis by inhibiting a

key enzyme in the metabolic pathway that produces that end product. For example, inhelping to control blood glucose levels, glucose-6-P inhibits the hexokinase enzyme that

allows phosphorylation of the glucose in the first place. This occurs in the muscles and

other tissues. On the other hand, glucokinase phosphorylates glucose in the liver, and the

kinase is not subject to feedback regulation. Because of this, and because glucokinasehas a high Km vs. that of hexokinase with a low Km, the liver is the major regulator of

plasma glucose levels.

There is a critical principle for you to absorb here. Please never forget this in all your

biochemistry-related courses. That is you can control an entire metabolic pathway, if you

control a key enzyme in that pathway. This is extremely thermodynamically efficient.Remember our Introductory Lecture. As we go along in biochemistry, we shall see that

many enzymes are simultaneously controlled by several mechanisms, in order to ensure

back-up or redundancy, as NASA calls it.

Before leaving the topic of enzyme inhibition, lets look at a few practical examples.

Now we all know that lead is a poison. Well, lead forms covalent (very tight bonding strong inhibition) bonds to the sulfhydryl groups of cysteines side chains in proteins,

including enzymes. This heavy metal shows the kinetics of non-competitive inhibition.

For example, the enzyme ferrochelatase, which catalyzes the insertion of Fe++ into a hemeprecursor, is quite sensitive to lead inhibition. Also, some insecticides irreversibly bond

to the enzyme acetylcholinesterase (thus neurotoxic effects). That they bond irreversibly

defines them as suicide inhibitors. Finally, more than half the pharmaceuticals used in

the U.S. are enzyme inhibitors. Both penicillin and amoxicillin inhibit enzymes involvedin the synthesis of the bacterial cell wall. Angiotensin converting enzyme (ACE)

inhibitors lower blood pressure by blocking this enzyme, which catalyzes the conversion

of angiotensin I to angiotensin II, a powerful vasoconstrictor. Enalapril and captopril areexamples of such drugs that induce vasodilation by this enzyme-inhibiting mechanism.

Enzyme Cofactors

Although some enzymes require no other molecules except their own amino acid


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sequence, many form associations with what we will call non-protein cofactors. Without

these cofactors, such enzymes would not be active. There are several types of cofactors.

The first group of cofactors is the inorganic elements. A given enzyme might require oneor more metals, such as Fe++ for the cytochrome oxidases (we will discuss these later in

the course), Mg++ for hexokinase and pyruvate kinase, Se, for glutathione peroxidase, and

Zn++

for carbonic anhydrase. Some of these might be present in the active site, beinginvolved with the catalysis, whereas others might play a structural role, for example.

Regardless, the need for trace metals in the diet is thus evident.

Also of critical importance is the group of cofactors called the coenzymes. They are

usually within the active site and usually participate in the actual catalytic reaction itself.

When tightly bound (covalently), any cofactor is referred to as a prosthetic group. Some

enzymes require both metals and coenzymes, in order to function. A complete,catalytically-active enzyme together with its bound coenzyme and/or metal ions is

referred to as a holoenzyme. The protein moiety of such an enzyme is defined as the

apoenzyme.

The topic of coenzymes is a large one, but a few principles should stay with you. First,

coenzymes are vitamin derivatives, as we shall see in a few examples to follow. Second,it is at the coenzyme where catalytic reactions take place. Your text on page 391 shows

the structure and reactive center of one of the very important coenzymes, nicotinamide

adenine dinucleotide (NAD+). This coenzyme is associated with oxidation/reduction

enzymes, such as the dehydrogenases, with which you will become familiar later in thecourse. For now, however, an oxidation/reduction reaction involves transferring

electrons and hydrogen, or in this case, a hydride ion. So picture this. You have the

entire complex enzyme structure with a coenzyme present in the active site, for the solepurpose of transferring a hydride ion and electrons from one substrate to another. The

same situation occurs with the coenzyme, flavin adenine dinucleotide (FAD+), another

coenzyme associated with the some of the dehydrogenase enzymes. See page 392 of

your text for its structure.

So why are cofactors necessary? We could say that the functional groups in proteins arelimited to whatever amino acid side chains are present. By joining with cofactors,

enzymes acquire more chemically reactive groups not available in the amino acid side

chains. The NAD+ molecules described above serve as a fine example of this point,

especially if you will examine the structure of NAD+. (Note: NAD+ represents theoxidized form, whereas NADH is the reduced form of the coenzyme.)

What an Enzyme Does to Facilitate Catalysis

The heading of this subtopic is the next question to be answered. What does this enzymeliterally do to speed up a reaction? There are two main answers, one an energy

consideration, the other more chemical. Lets tackle the latter point first by using the

digestive enzyme chymotrypsin as an example. We know this enzyme is designed to

facilitate the breakage of certain peptide bonds during digestion by a hydrolysis reaction.


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The enzyme cleaves polypeptide chains by breaking the peptide bond on the carbonyl

side of the amino acid residues that include an aromatic ring (such as in phenylalanine).

Briefly, a portion of the polypeptide enters the hydrophobic pocket of the active site withits hydrophobic side chain (aromatic ring), with the peptide bond to be broken opposite a

serine and histidine residue. Then a hydrogen transfers from the OH of serine to the

histidine. This allows formation of a strained (unstable) intermediate where the serineside chain bonds to the peptide bond carbon. The peptide bond is broken, and the

segment with the new amine group leaves the active site. Later a water molecule enters

the active site, and its H restores the H to the serine OH, while the OH of the water bondsto the other piece of the protein to give a new COOH terminal group, so that this piece

can leave the active site. I know this example is a little hard to picture without an

illustration; but it is very common and easily found on-line, if you wish. However, I am

not really interested in your learning the exact mechanism of peptide breakage as I am inyour getting the feel of what an enzyme is doing and how it is doing it. Now we can

make some general statements about how an enzyme really works.

So the enzyme 1) brings the substrate and catalytic sites together. This is called theproximity effect. It accomplishes this in such a way as to 2) bring the groups that must

connect close to each other by holding the substrate(s) at the exact distance and in theexact orientation necessary for the reaction. This is called the orientation effect.

Enzymes also 3) provide acid, basic, and other types of groups required for catalysis.

This is called the catalytic effect.

Having now explained a little about the chemical effects, we can now go to the final

explanation as to how enzymes work: the energy effect. This is where the energy barrier

for the reaction is lowered by the enzyme by inducing a strain in bonds within thesubstrate molecule, as mentioned above. Where the above-mentioned unstable strain in

the bond is just as it is about to break is called the transition state. Of course the same

principles apply to any reaction, where an enzyme, for example, might help bring tworeactants into position. Its the same principle. Lets look at an energy diagram and

observe the transition state, as well as other properties of the catalytic reaction.


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This graph is an energy diagram showing the energy change from a substrate (A) to a

product (B). The transition state is at the top of the energy diagram where the free energy

is the highest too high to be stable. Thus, the reaction proceeds to completion. Thinkof the transition period as being approximately the ES complex. The top G value is the energy of activation or energy barrier, which must be overcomefor the reaction to occur. Notice that the energy barrier is the energy differencebetween the initial state and the transition state. Notice how the enzyme lowers thisenergy barrier, compared to an uncatalyzed reaction. This energy barrier (energy of

activation) represents the proximity and orientation effects and other factors occurring

during the reaction. The G at the bottom of the graph i s the free energy yieldedfrom this reaction. Notice that the yield is the difference in free energy between thereactants and products. Notice also that by lowering the energy barrier, and thus

speeding up the reaction, we are not altering the value of the energy yield (or

requirement. This is very important,because that means we are not changing theequilibrium direction of the reaction with the catalyst. The enzyme (catalyst) only

speeds up a reaction but does not change the energy yield or energy requirement,

i.e. the direction of the reaction.

Additional Variables Related to Enzymes

As in the case of most proteins, there is an optimal temperature and an optimal pH at

which enzymes function. A bell-shaped curve would describe the activity or velocity of

an enzyme at a given temperature, with the optimal temperature (the top of the curve)being that of the body. The curve is plotted as velocity on the Y-axis vs. the temperature


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on the X-axis. Below the optimal temperature, the enzyme would function more slowly

and then progressively faster as the temperature rises. However, above optimal

temperature, there becomes an increasingly greater risk of denaturation of the protein,wherein the hydrogen bonds break and the proper geometric structure is lost. When you

fry an egg in a pan, you notice the change in the egg white. That albumin is being

denatured. Once the structure of the enzyme is compromised, then so is the function,especially in the case of an enzyme.

Likewise, each enzyme has an optimal pH at which it functions. However, unlike atemperature curve which would be similar for all enzymes each enzyme has its own

pH curve, which is bell-shaped, but which shows a varying optimal pH, depending upon

the enzyme. For example, trypsin, alkaline phosphatase, and pepsin all have bell-shaped

curves for enzyme velocity plotted against pH. However, the optimal pH for these threeenzymes is very different. Pepsin is a proteolytic enzyme designed to function in the

extreme acidity of the stomach. Thus, its optimal velocity is at about pH 1-2. Trypsin

has a maximal velocity at a pH closer to that of the approximately neutral pH

environment of the small intestine in which it functions. The bell-shaped curve for thevelocity alkaline phosphatase shows a maximal velocity (again, high point on the curve)

in the approximately mid-alkaline range. So, whereas the environment of the stomachwould denature trypsin and alkaline phosphatase, pepsin is so configured to function at

maximal velocity at the extremely acidic pH of the stomach.

The mechanism of the effect of pH on enzyme velocity is not difficult to understand.Think back about what you learned concerning pKa and ionization. Depending upon the

pKa of the respective reactive groups within the active site, pH changes will cause

ionization changes, which in turn will affect the bonding environment betweencomponents within the active site and between the active site and a potential substrate.

This can greatly affect the efficiency (and thus velocity) with which an enzyme functions.Zymogens

Briefly, this topic refers to the fact the many proteins are synthesized as precursors or in

an inactive form. Collectively, they are called zymogens in inactive secretory products(often in granule form) of a hormone- or enzyme-producing cell. These proteins are

activated later when in their proper environment. For example, many digestive enzymes

secreted by the exocrine pancreas are synthesized in an inactive state. One could only

imagine the pancreatitis that would follow, should the pancreatic enzymes be active whenthey are synthesized within that delicate organ. However, they are synthesized in the

inactive form, and they are activated only when they reach the duodenum. This

activation in some cases is pH driven, whereas in other cases, it involves removal ofsome key peptides by another already-active enzyme. In other words, depending upon

the enzyme, many of these catalysts, as well as other proteins (remember insulin), are

synthesized without activity, until later, when a pH-induced or enzyme-induced structuralchange initiates activation.


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Isoenzymes (also called Isozymes)

These can be defined as enzymes found in different tissues catalyzing the same reaction.

However, their physical properties vary, due to genetically programmed changes in their

amino acid sequence. Such amino acid changes are usually minor, but they are usuallydiscernable by electrophoresis, which you remember recognizes charge variations (due to

amino acid side chain differences). An example of an isoenzyme is hexokinase

(phosphorylating glucose in the muscle, for example) vs. glucokinase (phosphorylatingglucose in the liver.

Different organs often have different proportions of the isoenzymes. When a given tissue

is damaged, the normal plasma levels of a given isoenzyme unique to that given organwill usually rise. This is obviously of great diagnostic importance. For example, heart

muscle contains a creatine kinase (CK) isoenzyme (CK-MB). During and after a

myocardial infarction, many substances leak out of damaged or dead cardiac muscle,

including the CK-MB isoenzymes. Thus, the proportion of plasma CK-MB rises incomparison to the plasma levels of skeletal muscle (CK-MM) and brain (CK-BB)

isoenzymes. I am sure this topic will be discussed in greater detail in ClinicalBiochemistry, 560D.

Concluding Remarks

I have given a good bit of detail in this lecture. If you have any problems understanding

any aspect of it, please let me know quickly. In what I have presented, I am not trying tomake biochemists out of you. Believe me, the work would be much more intense and

would require a great deal of math. However, one of several of my goals in this course,

as I have previously stated (but wish to reiterate), is for you to understand what is goingon in the biomolecular world and why and how it is happening. Within the limited scope

of this single course, I want you to have an appreciation of some of the complexities and

inter-relationships that exist in biochemistry, and specifically here, enzymes. I nevercease to be in awe that the cell carries on all the activities it does - and with relatively

remarkable success. I need you to memorize, yes; but I also desire that you understand

and appreciate what biochemistry is really all about, that is, critical thinking and

understanding inter-relationships within the proper context. I hope I am beginning tosucceed.

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Week Five Lecture 560B on Line