Ethanol Metabolism and the Transition from Organic Chemistry to

In the Classroom edited by

Concepts in Biochemistry

William M. Scovell

Ethanol Metabolism and the Transition from Organic Chemistry to Biochemistry

Bowling Green State University Bowling Green, OH 43403

Richard D. Feinman Department of Biochemistry, SUNY Downstate Medical Center, Brooklyn, NY 11203-2098; [email protected]

The transition from organic chemistry to biochemistry entails several educational problems. Students in a medical or graduate biochemistry course may not have taken an organic chemistry course for two or three years. Many of these students approach the subject without good recall of the generalizing power of functional groups and have the expectation of extensive memorization of individual reactions. In the undergraduate organic course, students frequently have the perception that biology is somehow separate from chemistry and an abrupt adjustment must be made when biochemistry is introduced in the later sections. It is proposed here that the early introduction of the alcohol dehydrogenase and aldehyde dehydrogenase reactions can ease the transition from organic to biochemistry. The reactions involve three of the simplest compounds: ethanol, acetaldehyde, and acetic acid. These functional groups occur widely in biochemistry and many reactions can be seen as variations of the original theme. Methanol poisoning, for example, can immediately be taught as a reiteration of the basic scheme. There are three contexts in which this approach can profitably be used. First, in the beginning of a biochemistry course, it can be presented in the first lecture as a review of organic chemistry leading into the introductory section of biomolecules. Second, at the beginning of the metabolism section, introducing alcohol oxidation provides a model reaction that can be used as a recurring theme. Variations of the theme appear in carbohydrate and energy metabolism. In addition, when alcohol metabolism is ultimately taught in detail in the section on metabolic integration, many of the fundamental features are already known. Finally, this method has successfully been followed in the biochemical section of an undergraduate organic course to emphasize which reactions from previous semesters are important. In practice, I have found that this approach receives positive verbal feedback and, based on student questions, is successful in encouraging the conceptual learning of metabolic pathways. Step 1. The Alcohol Dehydrogenase and Aldehyde Dehydrogenase Reactions The oxidation of ethanol is presented as partial reactions: O

[O] CH3CH2OH

CH3 C

[O]

O CH3 C

H

OH

(1)

Students are told that when they ingest alcohol (ethanol) it is oxidized to acetaldehyde in the liver. The acetaldehyde is further oxidized to acetic acid and the acetic acid is then used for the generation of energy. For students who may already know some metabolism from elementary biology, it can be pointed out that the acetic acid is converted to acetyl CoA and enters the Krebs cycle, a process with which they may be familiar. In a first-year medical school or graduate course, sequence 1 establishes the three important functional groups, alcohol, carbonyl (aldehyde), and carboxylic acid, that need to be recalled from organic chemistry. Similarly, in the final section of an undergraduate organic course, it can be emphasized that these are key groups from the previous semesters. Step 2. How Do You Know It’s an Oxidation? Half reactions 1 define the first goal of identifying the three most important groups for students to recall. To characterize the reactions, the concept of oxidation–reduction reactions is reviewed. The value of the traditional system of assigning oxidation numbers and its application to biochemistry has been well summarized in a recent paper in this Journal (1): carbons atoms are assigned +1 for each bond to oxygen and ᎑1 for each bond to hydrogen. It is shown that reactions 1 constitute a progression from an oxidation state of carbon-1 from ᎑1 to +1, and then to +3. This practice is not without criticism. Calzaferri, for example, has pointed out the limitations of the traditional assignment of ᎑1 to atoms for bonds to hydrogen (2). Among the problems are that hydration of a double bond appears to be an oxidation and, as in the reaction at hand, unrealistically large changes in oxidation state are calculated. However, given the involvement of hydrogen transfer in biological redox reactions, it is virtually impossible to avoid this system if the idea of oxidation state is to be used at all. Reactions frequently involve movement of H+ with electrons or are hydride transfers. In my experience, students are willing to accept oxidation number as a convenient approximation, and it has the great heuristic value of allowing students to identify redox reactions easily. Especially important in the transition to biochemistry is the nomenclature of many oxidoreductases as dehydrogenases, which provides an easy way to identify oxidized and reduced species. (Hydration is usually rationalized by indicating that one carbon is oxidized and the other, reduced.)

JChemEd.chem.wisc.edu • Vol. 78 No. 9 September 2001 • Journal of Chemical Education

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In the Classroom

Step 3. The NAD+/NADH Redox Couple and the Transition to Metabolism At the beginning of the metabolism section of a biochemistry course, students will presumably have been exposed to enzymes and coenzymes and the next topic should present no problems. In the context of the introduction to the biochemistry course or in the organic course, however, a conceptual overview of enzymes and coenzymes is necessary and this is one of the more difficult parts of the regimen proposed here. The key is to make it clear that the coenzyme is a reactant (i.e., a small molecule) and the enzyme is the catalyst and a macromolecule. These ideas are best presented graphically; the level of sophistication will depend on the particular course. The idea of a catalyst can be related to organic reactions and illustrated with graphics of, for example, hydrogenation of alkenes on metals. For the role of the coenzyme, a good introduction, especially in the organic course, is to remind students that, for the kinds of oxidations in half-reaction 1, there were specific oxidizing agents such as KMnO4 or dichromate. Similarly, if they wanted to reduce something—for example, to go from acetaldehyde back to ethanol—they had specific reducing agents such as NaBH4. These were usually drastic reactions; that is, they went in one direction. Now, what’s different about biochemistry? In biochemistry, the oxidizing and reducing agents may be the same molecule (coenzyme), which can exist in an oxidized state (no hydrogen) or a reduced state (with hydrogen): the coenzyme is an oxidizing agent in its oxidized form and a reducing agent in its reduced form. Another way of saying this is that most oxidation–reduction reactions in biochemistry occur in steps that are more or less reversible. I have found that nomenclature is, in fact, a problem. Many students have the idea that “coenzyme” is a precise term and that a coenzyme is fundamentally different from a substrate. The coenzymes introduced here are NAD+ and NADH, which, because they are solution substrates, are most easily visualized; some authors use the term “cosubstrate” for coenzymes, such as NAD, that are not tightly bound to enzymes (1). Once the structure and mechanism are shown, further discussion can continue at the level of acronyms. The overall reaction is then written: NAD+

NADH + H+

NAD+

NADH + H+

CH3CH2OH

alcohol dehydrogenase

CH3

C H

Step 5. Variations on the Theme: Methanol Poisoning

O

O aldehyde dehydrogenase

CH3

C OH

(2)

Step 4. Alcohol Metabolism and Consequences of Alcoholism Equation 2 should be presented to students as the critical reaction for the work that follows. It defines three of the most important functional groups in biochemistry and is a model reaction for other metabolic processes to be studied. The example is also a process familiar to students as a nutritional or medical problem. As noted above, the liver metabolizes ingested alcohol by reactions 2. It can be made explicit that acetic acid is a precursor of compounds that ultimately provide energy; in

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this sense, alcohol is a “food” and a source of calories. Heavy drinking (considered to be regular consumption of more than two drinks per day [3]), of course, has serious deleterious effects—in addition to inebriation. The first oxidation product, acetaldehyde, is very reactive and can form several toxic products, especially by nucleophilic attack of amino groups of proteins on the carbonyl group. Also, if aerobic oxidation of acetic acid cannot keep up with continued alcohol intake, acidosis (excessive blood acidity) may result. Most important, the instructor should point out that the utilization of food is altogether an oxidative process and, since the two steps of sequence 2 are oxidations, the oxidized form of the coenzyme, NAD+, becomes depleted, and other aspects of metabolism may become compromised. The idea is necessarily vague at this point, but students appreciate the notion that the redox system is in imbalance. When normal metabolic processes cannot keep up with the intake of ethanol (blood concentrations greater than 1 mM), the body has reached the point where alcohol is no longer a food and has become a drug, and other oxidative processes (involving cytochrome P-450) become involved. Details should be left for the reprise of the subject at the end of metabolism, but it is worthwhile to raise the question of normal and abnormal ethanol intake. Finally, although increased aldehyde and acid are seen in most tissues, the liver is the major site that reflects alcohol abuse. Terms that may be familiar to students and can be put in a more precise context refer to the degrees of liver damage that can be due to alcoholism. In order of severity and irreversibility, these are fatty liver, hepatitis, and cirrhosis (3). An important point related to the importance of eqs 2 is that if aldehyde dehydrogenase is not active, acetaldehyde will build up. People lacking this enzyme or having a defective enzyme cannot consume alcohol because of the severe reaction to the buildup of acetaldehyde. This phenomenon is exploited in the design of the drug disulfiram (Antabuse), a negative reinforcement for behavioral control of alcoholism. Disulfiram is a covalent inhibitor of the aldehyde dehydrogenase. The use of disulfiram is covered well in both organic chemistry and biochemistry texts, although frequently as a “side-bar” or at the end of metabolism where alcohol processing is usually discussed (3–6 ).

One of the aims of the present approach is to highlight the generalizing effects of functional groups by using a specific example. With reactions 2 established as the major theme, methanol poisoning is an effective variation for emphasizing the systematic nature of organic reactions. Since it is structurally similar to the normal substrate, methanol competes for the active site of alcohol dehydrogenase. Likewise, the product, formaldehyde, is a substrate for aldehyde dehydrogenase, as well as for several other oxidative enzymes. Students are thus introduced (or reintroduced) to the concept of competitive inhibition, in this case, by competitive substrates. The principle is clear: competitive inhibition is an expression of the similarity of compounds with the same functional group. It is probably not overdoing it to emphasize that if you know reaction 2, you know reaction 3.

Journal of Chemical Education • Vol. 78 No. 9 September 2001 • JChemEd.chem.wisc.edu

In the Classroom

NAD+

NAD+

NADH + H+

NADH + H+

O CH3OH

methanol


H C

O H C

H

aldehyde dehydrogenase

formaldehyde

OH

(3)

formic acid

From the medical standpoint, the major concern is the reactive intermediate, formaldehyde—and especially its local generation in the eye, which contains an alcohol dehydrogenase. Formaldehyde reacts with nitrogen nucleophiles, and reaction with proteins of the eye can lead to blindness. The major contribution is local, since formaldehyde poisoning does not generally cause blindness [3, 7 ]). In addition to exacerbating the damage to the retina, the subsequent generation of formic acid leads to acidosis. If methanol poisoning is suspected, patients are given intravenous ethanol to compete with the methanol, which can be excreted; acidosis, if present, is corrected with bicarbonate while a test for methanol is made. If methanol is detected, current treatment favors dialysis. Several textbooks discuss this reaction, but again, as a special example toward the end of metabolism. Competitive reactions are well treated in organic and biochemistry texts, and in at least one text, methanol inhibition is used as the illustration for competitive inhibition (6 ). Note on test questions: because of the generally low specificity of alcohol dehydrogenase, the metabolism of other toxins follows the same pattern. Exam questions can test the ability to generalize this concept. Both isopropanol and ethylene glycol poisoning occur and an appropriate question would ask students to predict the corresponding carbonyl compounds (acetone and glycolaldehyde [hydroxyacetaldehyde], respectively). Summary and Continuation Teaching the early steps of ethanol oxidation as outlined above can ease the transition to biochemistry. The particular continuation will depend on the context. In the biochemistry section of an organic course, for example, carbohydrate chemistry is traditionally the first topic. Although instructors may take this for granted, it is important to emphasize that sugars are expected to have the properties of both carbonyl and hydroxyl compounds. In the same way, the oxidation–reduction reactions involving ethanol and acetaldehyde provide models for the redox reactions of carbohydrates. A simple example, although one that is rarely taught, is the interconversion of fructose and glucose through the intermediate reduction to glucitol (sorbitol). This can be presented directly after the structure of carbohydrates. The reaction is described in Reprise 1. This reaction has the advantage that, unlike most biological examples from carbohydrates, the reactants and products are not phosphorylated (a possibly distracting feature). The traditional laboratory oxidation and reduction of aldoses to aldonic acids and alditols should be compared to the enzymatic reactions. This is described in Reprise 2. In the biochemistry course, reactions 2 establish the functional groups that must be recalled from organic chemistry. With the addition of amines, they lead to the presentation of biomolecules, a common introductory topic. The study of enzymes, which is usually taught toward the beginning of

the course, is also facilitated by having a real example at hand. Methanol poisoning, for example, illustrates competitive inhibition. The alcohol dehydrogenase reaction can also be brought back as a model reaction in the metabolism section of the biochemistry course. This section usually begins with bioenergetic. In many cases the TCA cycle is presented first, since it is the major source of energy. If this route is taken, once the concept of high-energy acyl and phosphoryl transfer reactions is introduced, the conversion of acetic acid (from ethanol oxidation) to acetyl CoA can be described. This is a logical lead into the TCA cycle and students find it more palatable than having acetyl CoA presented cold. The instructor points out that the major source of acetyl CoA is from the processing of glucose, but that ethanol can also be a source—for alcoholics, sometimes the major dietary source. Ideas about the bioenergetics of redox reactions can be highlighted by reference to the reactivity of aldehydes (discussed in Reprise 4). If glycolysis is presented first, the comparison between aldehyde dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase provides a useful method for teaching substratelevel phosphorylation. This is outlined in Reprise 3, which also shows how it is possible to demonstrate the connections between glycolysis and lipid metabolism—again, by using the alcohol → carbonyl → carboxylic sequence as a model. The following is a summary of the way the fundamental reactions 2 can be brought back to emphasize the generalizing nature of organic reactions in biochemistry. Reprise 1. The Polyol Reaction The synthesis of fructose by conversion of glucose to glucitol (sorbitol) followed by reoxidation (reaction 4) represents another variation on the alcohol–carbonyl oxidation scheme. O HC H HO

CH2OH OH H

H

OH

H

OH

H NADPH + H +

NADP +

HO

aldose reductase

H

H

H

OH CH2OH

Sorbitol (Glucitol)

(4)

CH2OH C

OH

OH

OH

Sorbitol (Glucitol)

CH2OH

H

OH

CH2OH

Glucose

HO

H

H

CH2OH

H

OH

NAD +

NADH + H +

HO H

sorbitol dehydrogenase

H

O H OH OH

CH2OH

Fructoseee

This reaction is also an appropriate place to introduce reductases and NADPH (i.e., variations on dehydrogenases and NADH that occur in a particular context [biosynthesis]). Usually, if the polyol reaction is presented in biochemistry courses at all, it is presented as a somewhat specialized point in metabolism (a “side-bar” clinical correlation; see e.g., refs


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In the Classroom

4 and 6 ). Because of its educational value in reinforcing the central theme, it may be desirable to give it more attention. In an organic course, I have used it in the discussion of redox reactions of sugars and students find the clinical discussion interesting. The reactions are tissue specific—fructose is the preferred substrate of sperm cells, for example. The major organ of medical importance is the eye. High levels of glucose, as in diabetes, can lead to a buildup of glucitol in cells, such as lens and retina, that do not require insulin for glucose transport. If the sorbitol dehydrogenase cannot keep up with these levels, there will be an increase in osmotic pressure. Note on test or study questions: the net isomerization in the polyol reactions can be a model for students to understand the logic of other metabolic sequences. I have used the following as a “thought question” on an exam. Recall that epimers are isomers of simple sugars that differ in the configuration of a single carbon. Galactose is the 4epimer of glucose and epimerases, not surprisingly, catalyze this reaction. (The actual substrate is 1-UDP-glucose but the UDP does not enter into the reaction and can be ignored for this problem). Epimerases are NAD-dependent enzymes even though no oxidation takes place in converting UDPglucose to UDP-galactose. Write a mechanism for epimerases that explains how NAD+/NADH could function in the reaction.

The answer is that glucose is oxidized at the 4 position (by NAD+) to 4-oxoglucose, destroying the chirality at that carbon. Re-reduction by NADH leads to both epimers. In discussing the answer, one should point out that this is the “reverse” of the polyol reaction. In that case, reduction and re-oxidation lead to net isomerization of glucose to fructose.

Reprise 3. Glycerol-3-phosphate Dehydrogenase The most novel and successful use of the sequence alcohol → aldehyde → carboxylic acid as a teaching tool is in the study of glycolysis and its interaction with lipid metabolism. The second part, from glycolysis, glyceraldehyde-3-phosphate → 1,3-bisphosphoglyceric acid → 3-phosphoglyceric acid, is a sequence that students frequently commit to memory by brute force without good understanding of the rationale. Comparison with the model reaction can facilitate teaching the logic of substrate-level phosphorylation. The reaction glyceraldehyde-3-phosphate → 3-phosphoglyceric acid is presented as a replay of the acetaldehyde dehydrogenase reaction (reactions 2 and 6). I have found it is important while writing the overall reaction to make it clear that the conversion of glyceraldehyde-3-phosphate to 3-phosphoglyceric acid is theoretical. That is, it does not take place directly. In fact, what we want to know is why it is done in two steps. I explain that oxidation of glyceraldehyde by NAD+ is highly exergonic, and if allowed to proceed directly to the acid, the energy would be lost as heat. In fact, substrate is oxidized to “the acyl level”, but the enzyme prevents water from forming the free acid. The hydroxyl group in reaction 7 is a heuristic device for showing this idea. Instead of hydrolysis, the dehydrogenase catalyzes attack by phosphate ion to produce 1,3bisphosphoglycerate. NAD+

CH3CH2OH

H HO

H

H

OH

H

OH

H NaBH4

HO H H

O

H

C

CH3

aldehyde dehydrogenase

H

OH H OH OH

Br2

HO H H

NAD+

NADH + H+

O

triosephosphate isomerase

glycerol-3-P dehydrogenase

P O H

O

(6)

glycerol-3-phosphate

O HC

O

HO NAD+

CH

NADH + H+

C

O H

O O

O H

CH

O

CH2

glyceraldehyde-3-P dehydrogenase

P O H

O

CH2

3-phosphoglycerokinase

O

P O H

O

glyceraldehyde-3-phosphate

3-phosphoglyceric acid

ATP

3-phosphoglycerokinase

(7) ADP

O O

O

H OH OH

O

O

OH HC

(5)

NAD

+

+

NADH + H

CH2OH

D-Glucitol

D-Glucose

(Alditol)

(Aldose)

HO

O C

O O O

O H

CH CH2

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acid (Aldonic acid)

H

O O H

P

CH2OH D-Gluconic

O

P

C

O O

P O

CH2OH

(2)

OH

C

HC

OH

C

glyceraldehyde-3-P dehydrogenase

HO

O

CH3


O H

O

CH2OH

NADH + H+

CH2 O H

CH2

In the undergraduate organic course, some of the reactions of simple sugars can be presented as variations on the central theme (reaction 5). The sequence alditol–aldose– aldonic acid is much easier for students to comprehend if they can compare it to the model, ethanol–acetaldehyde–acetic acid. Of course aldaric acids do not fit into this scheme, but if reaction 5 is understood, oxidation of carbon-6 is easily assimilated. A further variation allows comparison of enzymatic and laboratory reactions: fructose can be reduced by borohydride to give two products, glucitol and the 2epimer, mannitol. This can be compared to the reduction of fructose catalyzed by sorbitol dehydrogenase and NADH (reaction 3), which is stereospecific, a general feature of enzymatic catalysis.

NAD+

O

CH

Reprise 2. Alditols, Sugars, Aldonic Acids

NADH + H+

O H

Depending on the level of the course, the details of the enzymatic mechanism can be examined. The intermediate is


In the Classroom

a thiohemiacetal formed from the active site thiol. This is the species that is oxidized (to a thioester) and then attacked by phosphate. If previous discussions were appropriate, the instructor can point out that the free energy of this downhill oxidation is captured as a progression of “high-energy” compounds: thioester (acyl-enzyme), carboxylic-phosphate anhydride (1,3-bisphosphoglycerate), phosphate anhydride (ATP). In practice, I have found that this example is a real eye-opener for students and helps greatly in understanding glycolysis. Reprise 4. Glycerol-3-phosphate, Glyceraldehyde-3phosphate, 3-Phosphoglyceric Acid The generalization of the model reaction can be continued in the comparison of alcohol dehydrogenase to the reaction catalyzed by glycerol-3-phosphate dehydrogenase (in combination with triosephosphate isomerase), allowing a discussion of the link between glycolysis and lipid metabolism. Triacylglycerol synthesis and breakdown is one of the important topics in lipids but its relation to other aspects of metabolism is sometimes not sufficiently emphasized. Students tend to compartmentalize topics in metabolism, a problem that is probably best described by the title of the play satirizing guided tours, If This Is Tuesday, We Must Be in Belgium. The connection between lipid metabolism and carbohydrate metabolism, however, is critical in the physiology of adipose tissue. The absence of glycerol kinase in this tissue means that glycerol-3-phosphate, the substrate for triacylglycerol (TAG) synthesis, must be supplied by the action of glycerol-3phosphate dehydrogenase.1 The presence of glycerol-3-phosphate is, in this sense, a signal for TAG synthesis, and the reduction of glyceraldehyde-3-phosphate (via dihydroxyacetone phosphate) is the physiological link between glucose levels and the storage of fat. In the opposite direction, oxidation of glycerol transported from adipose tissue and phosphorylated in other tissues is a step in the utilization of fat for energy and the (very limited) utilization for gluconeogenesis. The formal relation between reactions 2 and the pathway glycerol-3-phosphate → glyceraldehyde-3-phosphate → 3-phosphoglyceric acid makes this interrelated system easier for students to learn. These reactions can also be tied to a discussion of the glycerol phosphate shuttle, which is where glycerol phosphate oxidation is usually studied. This is an appropriate place to discuss energetics. With several examples in hand, students can be reminded that aldehydes are reactive—easily reduced or oxidized. They can be reminded that they learned in organic chemistry that alcohols are oxidized all the way to the acid by common oxidizing agents and that to stop at the aldehyde, special compounds such as pyridinium chromate must be used. Similarly, if borohydride is used to reduce an acid, it also reduces the aldehyde to an alcohol. In the enzymatic case, oxidation of alcohol by NAD+ is endergonic but oxidation of acetaldehyde is exergonic. In combination with acetic acid utilization, this makes the overall reaction go forward. The exergonic oxidation of glyceraldehyde-3-phosphate can be appreciated as another example of this general principle. Reprise 5. The TCA Cycle An understanding of the oxidations of the TCA cycle requires more than generalizations from reactions 2. In

particular, the driving force of decarboxylations must be presented. It is to be hoped that using the central theme at this juncture will predispose students to look at the mechanism of the TCA cycle reactions in a systematic way. One example that can be seen as a more or less direct generalization of the oxidation of an alcohol is the malate dehydrogenase reaction. The reaction should be written in the lecture along with the alcohol dehydrogenase reaction; again, I think we tend to underestimate how much generalizations of functional group reactions are not immediately obvious to students. This is actually a slight variation of the original idea and it must be pointed out that the keto group of an α-keto acid is more easily reduced than a normal ketone—that is, it is more like an aldehyde. An important generalization can then be made: NAD+ is not a good oxidizing agent for this reaction and equilibrium favors malate, the reduced form of the metabolite. It is now reasonable that the malate → oxaloacetate conversion is the only endergonic oxidation in the TCA cycle, a fact that is otherwise learned by rote memorization. The importance of this point derives from the role of oxaloacetate in gluconeogenesis and in the final discussion of ethanol metabolism. Reprise 6. Generalizations from Bioenergetics and Redox Potentials Redox potentials and their use is one of the more difficult subjects in the biochemistry course. A major goal in studying redox potentials is to quantify ideas that are already known qualitatively, although this not always clear to students. If the principle is stressed that aldehydes, or activated ketones (α-keto acids), are reactive, the numerical values of redox potentials can reinforce this qualitative idea. More important, it can help “desensitize” students to the redox tables altogether. Thus, examination of a chart of standard redox potentials will show that the NAD+/NADH couple has a more negative potential (᎑0.32 V) than the carbonyl/alcohol couples that have been studied: acetaldehyde/ethanol (᎑0.20) and oxaloacetate/malate (᎑ 0.17). This means that NADH is a better reducing agent than alcohols and spontaneously reduces the carbonyl, as was learned qualitatively. Conversely, the acid/ aldehyde half-reactions have the more negative potentials relative to NAD+/NADH—acetate/acetaldehyde (᎑0.58); that is, acetaldehyde is spontaneously oxidized by NAD+. The meaning of the redox potential as a measure of the relative tendency of the reduced form to be a reducing agent can be stressed by this example. The intermediate nature of the NAD+/NADH couple can be discussed here as a preview of the most important example, which should be reiterated later: E0′ for NAD+/ NADH is intermediate between values for TCA cycle substrates and components of the electron transport chain. Final Reprise. Alcohol Metabolism The discussion of alcohol metabolism in biochemistry texts is generally very good (see e.g. refs 3–6 ). However, the topic traditionally comes at the end of metabolism—whereas with the method suggested here, it appears at the beginning and runs throughout as an undercurrent. An advantage to this approach is that some biological implications of alco-


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In the Classroom

holism that are difficult to understand when confronted for the first time are already in the student’s mind. For example, the knowledge of the buildup of NADH and its implications does not have to be pondered. Students are made aware, in the first presentation, that two oxidations occur and there will be a shortage of oxidizing agent, NAD+, and an excess of NADH. To regenerate NAD+, there will be an increase in production of lactic acid, which accounts for the major part of the acidosis in alcoholics. The concept of relative reactivities in oxidation, which is developed throughout the course, leads to an understanding of the basis for the unfavorable equilibrium (with respect to oxaloacetate) in the malate dehydrogenase reaction. The unfavorable equilibrium, in combination with excess NADH, makes oxaloacetate unavailable for gluconeogenesis. The possibility that an alcoholic may become hypoglycemic can now be understood at a biochemical level. Prior exposure to these concepts makes it easier for students to understand the logic of the process. Conclusions The initial steps in the oxidation of alcohol provide the basis for a review of the most important functional groups in biochemistry and they also provide a model for a number of reactions in intermediary metabolism. Moreover, the constant repetition ensures that at least reactions 2 will be one idea that students take away from the course. I have used this method in graduate and medical school biochemistry and in the third quarter of an organic chemistry sequence. Verbal feedback suggests that it is helpful to many students and that the desired goal of reducing memorization of isolated organic reactions can be achieved.

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Acknowledgments I am grateful to Robert Cohn of Children’s Hospital of Philadelphia and David Essex of Downstate Medical Center for information on ethanol and methanol metabolism. For criticism and suggestions on the manuscript, I thank Steven Young of Downstate Medical Center and Janis Lull of the United States Open University. Note 1. Dihydroxyacetone phosphate is also a substrate for the acyl transferase. The resulting product must be reduced in the next step but this variation is more confusing than helpful to students and need not be introduced here, or possibly at all, in the elementary biochemistry course.

Literature Cited 1. Halkides, C. J. J. Chem. Educ. 2000, 77, 1428–1432. 2. Calzaferri, G. J. J. Chem. Educ. 1999, 76, 362–363. 3. Cohn, R. M.; Roth, K. S. Biochemistry and Disease; Williams & Wilkins: Baltimore, 1996. 4. Devlin, T. M. Textbook of Biochemistry with Clinical Correlations, 4th ed.; Wiley: New York, 1997. 5. Baynes, J.; Dominiczak, M. H. Medical Biochemistry; Mosby: London, 1999. 6. Champe, P. C.; Harvey, R. A. Lippincott’s Illustrated Reviews: Biochemistry, 2nd ed.; Lippincott: Philadelphia, 1994. 7. Winchester, J. F. In Clinical Management of Poisoning and Drug Overdose; Haddad, L. M.; Shannon, M. W.; Winchester, J. F., Eds.; Saunders: Philadelphia, 1998; Chapter 35.


Ethanol Metabolism and the Transition from Organic Chemistry to

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