Chemistry of Beer – Unit 2 – Chemical Concepts: Alcohol Metabolism

By Brian Lemay 2 comments


>>Dr. Paul Sims: Welcome to this segment of
the chemistry of beer. In this segment we’ll be discussing alcohol metabolism. As you know,
in this country the legal drinking age is 21, and at that time people make a decision
whether or not they want to drink alcohol. I think it’s important, therefore, that people
understand how alcohol is metabolized in our bodies, and therefore, I think this topic
will be relevant and interesting for everyone. To outline what we’ll be talking about, I
want to first of all talk about the chemical properties of the alcohol that’s in alcoholic
beverages. Then we’ll give a few preliminaries about blood alcohol concentration. Finally,
we’ll discuss enzyme-catalyzed reactions, those that are responsible for for metabolizing
the alcohol. And then at the end we’ll try to tie together a few loose ends and give
a summary of what we discussed. As some of you may already know, the particular
type of alcohol that’s present in alcoholic beverages is ethanol. Ethanol has the formula
CH3CH2OH, and it is introduced into beer through the action of yeast. Ethanol is a relatively
small molecule. It has a molecular weight of 46. It’s amphiphilic in that it has a nonpolar
end and a polar end, and it is completely miscible in water. Sometimes people refer
to it as being infinitely soluble in water. Another interesting feature of ethanol is
that it passes through membranes readily, and it can penetrate the blood-brain barrier. The next topic I wanted to discuss was blood
alcohol concentration, which I’ll be referring to as BAC. There are several factors that
determine what a person’s BAC will be after he or she consumes an alcoholic beverage.
Some of these factors include: one, how rapidly the alcoholic beverage was consumed; two,
how much food the person has in their stomach; three, the size of the person; and four, how
rapidly a person is able to metabolize ethanol. That is the subject we’re going to move into
next–metabolizing ethanol. Continuing with our topic of blood alcohol concentration,
or BAC, we want to think about properties of enzymes, and in particular, some of the
properties of enzymes that metabolize ethanol. Because enzyme parameters such as Km, or the
Michaelis constant, which we’ll discuss shortly, because these terms are given in in terms
of concentration, such as millimolar, but alcohol concentrations are typically given
in terms of percent volume, it is important for you to be able to make some basic conversions
so that you can answer questions, such as: “What is the millimolar concentration of alcohol
in the aqueous portion of the human body after a person has consumed a 12 ounce beer that
contains 6% volume volume of alcohol? Assume that alcohol is fully distributed and is not
begun to be metabolized or excreted, and here’s a hint: you can consider that the human body
contains about 40 L of water.” And please note that there are several ways to solve
this problem, but one thing you might want to do is look up the density of ethanol. Our next topic is to answer the question:
where is the ethanol metabolized? The liver is the primary site of ethanol metabolism,
although some ethanol metabolism also occurs in the gastrointestinal tract, the pancreas,
and the brain. There are three enzyme systems that are responsible for metabolizing ethanol.
The first enzyme system is alcohol dehydrogenase, which I will abbreviate as ADH, and aldehyde
dehydrogenase, which I will abbreviate as ALDH. Combined, ADH and ALDH process about
80 to 90% of the ethanol that a person consumes. Another enzyme system is the cytochrome P450
enzyme complex. This is comprised of cytochrome P450 reductase and CYP2E1. This enzyme system
processes about 10 to 20% of the ethanol that a person consumes. The last enzyme system
that metabolizes ethanol is catalase. This is fairly minor except in the fasted state. We’re now going to talk about each of these
enzymes in a little more detail. And so the first enzyme that we’re going to start with
is alcohol dehydrogenase, or ADH. If we consider the ADH reaction, we see that we start with
ethanol and something called NAD+, which I’ll talk more about in a minute. And we have an
equilibrium arrow, a double-headed arrow. And underneath that, we’ve written ADH, and
that’s to signify alcohol dehydrogenase. We see that we form a molecule called acetaldehyde,
and then we form NADH, and we also form H+, or a hydrogen ion, or if you want, a proton.
There are a few interesting features of ADH that you should be aware of. First of all,
ADH is found in the cytosol of liver cells or sometimes called hepatic cells, and there
are many isoforms of this enzyme. The NAD+ and the NADH stand for nicotinamide adenine
dinucleotide, oxidized and reduced forms, respectively. And since that’s kind of a mouthful,
you can see why we just refer to them as NAD+ or NADH. Then finally the acetaldehyde that is produced
by the ADH reaction is very toxic, and that points to the need for another reaction that
can further metabolize acetaldehyde. And that is the aldehyde dehydrogenase reaction, or
the ALDH reaction. So the next enzyme that we’re considering is the aldehyde dehydrogenase
enzyme, or ALDH. As you can see from the reaction scheme, we start with the product of the alcohol
dehydrogenase reaction, which is acetaldehyde. That’s that toxic molecule that needs to be
further metabolized before it can do significant damage. So we start with acetaldehyde and
NAD+ again and water, and this time the aldehyde dehydrogenase catalyzes the formation of acetate
and NADH and liberates two hydrogen ions, or two protons. You should be aware that there
are cytosolic and mitochondrial forms of aldehyde dehydrogenase. Similar to what we saw with
alcohol dehydrogenase, aldehyde dehydrogenase also converts NAD+ to NADH as it converts
the substrate (acetaldehyde) to the product (acetate). We’re going to be seeing NAD+ and
NADH quite a bit, and so I want you to key in on those two molecules. Finally, the acetate that is produced can
be metabolized further to carbon dioxide and water, or it can serve as a precursor for
fatty acid biosynthesis. In addition to abbreviating nicotinamide adenine dinucleotide as NAD+
or NADH, I also want to explain why I’m not going to be showing the chemical structure
of these molecules every time. As you can tell from this figure, NAD+ and NADH are reasonably
complicated molecules, and it would take too long to draw them every time, so that’s why
we’re going to stick with the abbreviation NAD+ and NADH. The second enzyme system that metabolizes
ethanol is the cytochrome P450, and that will be the topic of this discussion. As you can
see from the diagram, we start with ethanol. This time we start with, in addition to ethanol,
NADPH. This is very similar to NADH. There’s just the difference of whether or not a phosphoryl
group is attached to the molecule. We also include a hydrogen ion and oxygen, and then
the enzyme catalyzes the formation of acetaldehyde. And remember that’s toxic, so it needs to
be metabolized further by aldehyde dehydrogenase. We also form NADP+ and two waters as products.
The CYP2E1 is located in the lumen of the endoplasmic reticulum of cells, and what’s
interesting is it uses a heme cofactor. Now depending on your study of biology and
biochemistry, you may or may not have encountered heme before. But if you’ve talked about or
or read about the proteins hemoglobin and myoglobin, then you might be familiar with
what a heme cofactor is. For those proteins, hemoglobin and myoglobin, the heme cofactor
functions to carry oxygen, or or bind oxygen I should say. But in the cytochrome P450 enzyme,
the heme cofactor is actually used to help catalyze the reaction. Now CYP2E1 has a higher
Km, a higher Michaelis constant, for ethanol than does alcohol dehydrogenase. Thus, this
enzyme doesn’t really come into play until the ethanol concentration is relatively high. I’ve mentioned Km a couple of times now, and
before I get too much further, I think it’s important to take a minute and to to try to
illustrate what we mean by Km. If we look at this graph, we see a plot of velocity on
the y-axis as a function of substrate concentration. That’s the S in brackets on the x-axis. We
see that as we start to increase the substrate concentration, the velocity rapidly increases,
but as we go to higher substrate concentrations, the velocity begins to taper off and approach
an asymptote. Now that asymptote is the vmax, the maximal velocity of the reaction. What
the Km is is, it’s the substrate concentration that allows the enzyme to achieve half of
its maximal velocity. Graphically, we can see that by going to 25 micromolar per minute,
that’s half of our vmax, which is 50 micromolar per minute. And we move out from 25 micromolar
per minute until we intersect the the trace of the enzyme activity, and then we move straight
down until we intersect the x-axis, which reflects the substrate concentration. And
so we see that the Km is the substrate concentration that allows the enzyme to achieve half of
its maximal velocity. So if we go back to our discussion about cytochrome
P450, I mentioned that it has a relatively high Km, and that means it’s not very active
until the ethanol concentration is relatively high. So that’s an explanation for why ADH,
alcohol dehydrogenase, metabolizes most of the ethanol, because it has a lower Km. So
that means it can be more active at lower alcohol concentrations, rather than the cytochrome
P450, which needs higher ethanol concentrations to be active. The last enzyme that we’ll consider
in the metabolism of ethanol is catalase. As you can see from the diagram, catalase
catalyzes the reaction between ethanol and H2O2. H2O2, as you probably know, is hydrogen
peroxide. In the process acetaldehyde is formed, again that toxic molecule that is metabolized
further by aldehyde dehydrogenase, and we also form two waters. Catalase is found in
peroxisomes. And similar to cytochrome P450 or CYP2E1, catalase also contains a heme cofactor.
As noted earlier, this reaction plays a very minor role in alcohol metabolism, except if
someone is in a fasted state. We’ve seen that the alcohol dehydrogenase catalyzes the conversion
of ethanol into acetaldehyde, and acetaldehyde is toxic, so it is further metabolized by
the enzyme aldehyde dehydrogenase to the molecule, the product acetate. Our next topic is to consider what happens
to the acetate that’s produced. As you can see from this diagram, the acetate reacts
with ATP, adenosine triphosphate, that’s referred to sometimes as the energy currency of the
cell, and CoASH, and that stands for coenzyme A, and the SH is to indicate that it ends
with a thiol. The enzyme that catalyzes this reaction is called acetyl-CoA synthetase,
and the products of the reaction are acetyl-CoA, AMP (adenosine monophosphate), and PPI, which
stands for inorganic pyrophosphate. Much of the acetate that is formed as a result of
the aldehyde dehydrogenase reaction leaves the liver. It can then be taken up by the
heart, the brain, and the skeletal muscle, where it is further metabolized, initially
by the acetyl-CoA synthetase reaction. The acetyl-CoA that’s produced as a result of
the acetyl-CoA synthetase reaction can then enter the Tricarboxylic Acid cycle, or it
can serve as a precursor for fatty acid biosynthesis and cholesterol biosynthesis. We are going
to come back to the Tricarboxylic Acid cycle in a future video. So we’re pretty much done with our discussion
of ethanol metabolism, just have a few loose ends to to wrap up and then to kind of give
a brief summary. There are a few nonoxidative pathways that occur, but I opted not to mention
these pathways. There’s also something you should be aware of. The cytochrome P450 enzyme
reaction, it can generate reactive oxygen species, which are sometimes abbreviated as
ROS. These reactive oxygen species can damage cells by forming, for example, adducts with
proteins. And by the way, acetaldehyde can also form adducts with proteins. That’s part
of its dangerous, toxic effect. To summarize what we talked about, the liver is the primary
organ that metabolizes ethanol. Alcohol dehydrogenase is the primary enzyme that reacts with ethanol,
but CYP2E1, or cytochrome P450, and catalase also play a role. The aldehyde dehydrogenase
reaction converts toxic acetaldehyde to acetate, which can be broken down further to carbon
dioxide and water. Both the ADH (alcohol dehydrogenase) and ALDH (aldehyde dehydrogenase) reaction
form NADH. Please keep this in mind as we revisit this cofactor several times.

2 Comments

korikafez

Jan 1, 2016, 4:05 am Reply

Muchas gracias, hombre. Sharing this. Happy New Year.

Donald Huskey

Apr 4, 2018, 12:12 am Reply

Excellent explanation. Congrats. Thank You

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