Tuesday, April 17, 2007

Pyruvate

Pyruvate is a very important molecule in living cells. It was Monday's Molecule #22. It's important because it's one of the essential 3-carbon (3C) intermediates in biochemical pathways. It's required in both biosynthesis and degradation pathways. If you only have to know a few molecules in the cell then this one should be near the top of your list.

Let's start by learning a little bit of organic chemistry. The simplest organic molecule with only two carbon atoms is called ethane (CH3CH3). The one with three carbons is propane and the one with four is butane. The alcohols are called ethanol, propanol, and butanol respectively. The acids are ethanoic acid (CH3COOH), propanoic acid (CH3CH2COOH), and butanoic acid (CH3CH2CH2COOH). Ethanoic acid is more commonly known as acetic acid because it's found in vinegar and the Latin word for vinegar is acetum.

Pyruvate can also be called pyruvic acid. In a minute I'll explain why we call it pyruvate instead. It's related to propanoic acid (CH3CH2COOH) except that it has an extra oxygen on the middle carbon. The -C=O group is called a keto group and molecules that have it are ketones.

The proper chemical name for pyruvate is 2-oxopropanoic acid because it's propanoic acid with an extra oxygen (oxo-) on carbon atom #2. Keto acids usually have trivial names that aren't related to the names of the simple organic molecules and that's why pyruvate is the name everyone uses. The reason why keto acids are common in biochemistry is because they are quite reactive.

Acids are compounds that can easily give up a proton (H+). Protons are what makes an acid an acid. The more protons you have in solution the more acidic the solution will be. The term pH refers to the inverse of the concentration of H+. The lower the pH the higher the concentration of protons.

Pyruvic acid is an acid because when it's dissolved in water the proton from the carboxylate (-COOH) group dissociates leaving the negatively charged pyruvate and a free proton. The three components exist in equilibrium—that's what the double arrows mean. At any given time there will always be some pyruvic acid, some pyruvate, and some protons. The concentrations won't change because the dissociation/association reactions are at equilibrium.

The relative concentrations of pyruvic acid and pyruvate at equilibrium depend on the properties of the molecule and the conditions inside the cell. In this particular case we know for certain that there's very little pyruvic acid inside the cell. Almost all of the molecules are in the form of pyruvate. Pyruvate is the biologically significant molecule and that's why biochemists always refer to these molecules as acetate, pyruvate, butyrate, etc.

In all species, pyruvate is required for the synthesis of the amino acid alanine. It's also required for the synthesis of 6-carbon (6C) sugars such as glucose. In fact, you can think of gluconeogenesis (glucose synthesis) as just a series of steps where two pyruvate molecules are joined to make one glucose molecule (3C + 3C → 6C).

Pyruvate itself is synthesized from simpler molecules in bacteria. One common pathway is to add a carbon from carbon dioxide to a 2-carbon acetate molecule (1C + 2C → 3C). In plants and bacteria the primary product of the carbon fixing cycle (Calvin cycle) is a 3-carbon compound called glyceraldehyde 3-phosphate. It is rapidly converted to pyruvate.

Pyruvate can be activated to a phosphorylated derivative called phosphoenolpyruvate (PEP). PEP is a high energy compound used as an energy source in many reactions. (It has considerably more energy than ATP.) The direct conversion shown in the diagram below is confined to bacteria. In eukaryotes the conversion follows an indirect pathway.

There are many other fates of pyruvate as shown above. Pathways leading to synthesis of additional amino acids go through oxaloacetate. Oxaloacetate is also one of the components of the citric acid cycle. The synthesis of lipids and fatty acids requires acetyl-coenzyme A or acetyl-CoA, which is made from pyruvate in a reaction catalyzed by pyruvate dehydrogenase (more about this later—it's the main theme of this series).

Most students first encounter pyruvate as the end product of glycolysis. Glycolysis is the pathway for breaking down glucose. It is the opposite of gluconeogenesis because a 6-carbon compound is degraded to two 2-carbon compounds (6C → 3C + 3C). Even though this is a minor pathway in most kingdoms, it is important in animals and, most especially, in mammals like us. This is why glycolysis has traditionally received so much attention in schools. That's about to change.

In some species the accumulation of pyruvate leads to other pathways. One of them is synthesis of lactate, which often serves as a temporary storage depot for 3-carbon compounds. Another is synthesis of ethanol, which involves chopping off one of the carbons in the form of carbon dioxide (CO2) and excretion of ethanol. Humans love those species that excrete ethanol. Over several millennia humans have selected strains of yeast that do a very efficient job.

Nobody needs to memorize all the pathways involving pyruvate. Not even my biochemistry students. The point here is simply to illustrate the central importance of pyruvate so you'll see why it's something you should know about.

Of all the fates of pyruvate, the one that is most interesting is the conversion to acetyl-CoA. As mentioned above, acetyl-CoA is required for fatty acid synthesis but it also serves as the substrate for the citric acid cycle where the acetate part of pyruvate is fully oxidized to CO2. Note that the reaction catalyzed by pyruvate dehydrogenase not only makes acetyl-CoA but also accomplishes the first step in the complete oxidation of pyruvate to 3 molecules of CO2. The energy released in this breakdown is captured by NADH.

4 comments :

  1. One of my microbiology professors calls pyruvate: "beautiful pyruvate." That's even how she writes it on lecture notes.

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  2. Why is it that we can drink acetic acid in the form of vinegar (some people like to do this for health reasons), but it doesn't cause or blood pH to change? Or does it? I'm having trouble understanding what happens to acetic acid via oral consumption, then metabolism...Thanks for any clarification you can offer!

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    Replies
    1. There are several reasons. First, the acetic acid is absorbed as acetate and that's not a proton donor (i.e. not an acid). Second, acetate is quickly incorporated into other carbon compounds. Thirdly, the pH of your blood is buffered so it takes a significant amount of acid or base to change the pH.

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