Metabolism

I. Overview

>A. Definitions

>>1. Metabolism

>>2. Types of metabolic reactions

>>>a. Catabolism (think "catastrophe"- stuff gets broken down and energy is released, like in an earthquake)

>>>b. Anabolism

>B. The nutrients

>>1. Carbohydrates- energy, some structure. Review polysaccharides (starch, glycogen, fiber), disaccharides (maltose, sucrose, lactose) and monosaccharides (glucose, fructose, galactose)

>>2. Lipids- energy, structure and function. Review sterols, triglycerides and phospholipids.

>>3. Proteins- structure, function and energy (from amino acids)

>>4. Vitamins- organic molecules. Serve a variety of functions; some are coenzymes (activate enzymes). Other examples include antioxidants (V-E, V-C, V-A) and a hormone (V-D).

>>5. Minerals- inorganic, single ions. Serve a variety of functions; for example, you know the many functions of Ca2+, of Na+, K+, and phosphorus (as PO4-). Some other minerals include Fe2+, selenium, Cl-, Mg2+, manganese, copper, etc.

>>6. Water- you know the functions of water!

>C. The production of ATP- a backwards overview. This overview starts with the endpoint of ATP production: the point at which PO4- gets added to ADP (ADP is phosphorylated). It then moves "back in time," to see how we got to each event.

We know that, ultimately, the energy to make ATP comes from glucose, fatty acids, or amino acids. Why doesn't a cell just break the bonds in those molecules to do work? They have TOO MUCH energy for the cell to do normal work. In fact, if the cell were to release all the energy in, for example, glucose at once, too much heat would be released. The cell wouldn't be able to control the energy release, and wouldn't be able to use as much of the released energy (and would probably burn up). So, the cell very carefully extracts energy, bit by bit, and transfers it into small, portable batteries: ATP. Each ATP stores just the right amount of energy for the cell to do one job, like recock a myosin head for another muscle contraction.

>>1. Most ATP is formed in the mitochondria, during the process called the Electron Transport Chain. The ETC occurs along the inner membrane of each mitochondrion. In this inner membrane is a series of embedded proteins, including the enzyme ATP synthase. ATP synthase attaches PO4- to ADP, creating ATP.

>>2. The phosphorylation of ADP to make ATP requires energy. Where does that energy come from? It is provided by H+ ions rushing down their concentration gradient. Remember that a concentration gradient across a membrane is a form of stored energy. If you allow particles to move across the membrane, they will move from high concentration to low (kinetic energy). The cell has been busy pumping H+ to one side of the inner mitochondrial membrane, to establish a concentration gradient. It then allowed those H+ to rush down their gradient, through a tunnel in ATP synthase. ATP synthase then used the energy released by this mass movement to phosphorylate an ADP and make ATP.

>>3. We know that it takes energy to pump particles against their concentration gradient. And we know that the cell has been doing just that with H+ ions, to provide energy to ATP synthase. Now, where did the cell get the energy to establish this H+ concentration gradient?

From electrons. Electrons have kinetic energy, they constantly zip around. The cell is able to extract some of the energy from electrons.

>>4. How is the cell able to extract energy from electrons? By passing the electrons along the proteins that are embedded in the inner mitochondrial membrane. Each electron gets passed from the first protein, to the next, and so on. With each pass, the electron loses energy. I am able to grasp this concept by envisioning the electrons slowing down with each pass.

Another way to envision this is to think of the electrons as hot potatoes, and the proteins as people. Imagine that I passed a hot potato to your classmate Sunisa, and then she passed it to Devorah, then to Dereje, then to Libby, and so on. With each pass, the potato loses heat (or energy).

Anyway, it is the energy lost when electrons are passed along these proteins that is used to drive H+ ions across the inner mitochondrial membrane. These proteins are electron acceptors.

We will discuss where those electrons end up when we revisit ATP production from the beginning to the end.

>>5. Where do the electrons come from? Hydrogen atoms. H is composed of one proton (+) and one electron (-). At the beginning of the ETC, a H is stripped of its electron, leaving a H+ (proton) and e- (electron).

>>6. Where do the H atoms come from? They are extracted from molecules during the other processes of ATP production: glycolysis and the TCA cycle. Most of them come from the TCA cycle, which also occurs in mitochondria.

>>7. How do H get from the TCA cycle & glycolysis to the ETC? By the molecules NAD+ and FAD. These two molecules act as "shuttle vans" for H. They pick up H as they are released from molecules in the TCA cycle, and shuttle them to the ETC. When NAD+ carries two H, it's called NADH + H (your book just uses NADH, so I will too). When FAD carries 2 H, it's called FADH2. So, NAD+ and FAD pick up Hs from the TCA cycle, and bring them to the ETC. They drop the Hs off, and then the Hs are stripped of their electrons.

NADH and FADH2 are considered "high energy compounds" because they are carrying energy in the form of electrons in the H. Technically, we say that they carry electrons rather than H, because it's the electrons that have the energy we're interested in. NAD+ is partially composed of the B-vitamin niacin, and FAD is composed partially of the B-vitamin riboflavin.

>>8. How are H released from molecules during the TCA cycle? The TCA cycle (also called the Krebs or Citric Acid cycle) is a cyclical series of chemical reactions. In the first step of the TCA cycle, a 2-carbon molecule called acetyl was added to a 4-carbon molecule called oxaloacetate. Both molecules contain H. When acetyl is added to oxaloacetate, they form a 6-carbon compound called citric acid. Citric acid then goes through a series of very carefully controlled reactions.

During those carefully controlled reactions, the H and O of citric acid are rearranged along the carbon backbone. By doing so, the cell is able to allow some of the H to be released, while still maintaining stable molecules. Water is used during some of the reactions. In two reactions, a carbon and 2 oxygens are removed, and expelled as waste (CO2).

After the 2 carbons are removed, and H are removed, the end result of all of the carefully controlled reactions of the citric acid cycle is oxaloacetate, which is ready to react with another acetyl! Hence the name "cycle." So, acetyl provides H for the ETC. The complex TCA cycle allows those Hs to be removed carefully, so that no unstable molecules are made in the process.

Some energy is released as bonds are broken during the TCA cycle, and the cell is able to harvest some of it to make a couple of ATP.

>>9. Where do the acetyls come from? The molecule pyruvate, which contains 3 carbons, some Hs, and some Os. Pyruvate is converted to acetyl when a C and 2 Os are removed and expelled as waste (CO2). During this conversion, a H is also removed (which will be picked up by NAD+). The conversion of pyruvate to acetyl also occurs in mitochondria.

Acetyl is not a whole molecule; one of its carbons contains only 3 bonds. Acetyl will move quickly to the TCA cycle, but it needs to be stabilized on its way. The molecule coenzymeA (coA) bonds with that carbon, stabilizing acetyl. When coA is bound to acetyl as it moves to the TCA cycle, it is called acetyl coA. Incidentally, coA is derived from another B-vitamin.

>>10. Where do the pyruvates come from? Glycolysis. Remember that during glycolysis, a 6-carbon glucose is split into 2 3-carbon pyruvates. Energy is released during glycolysis, and the cell is able to harvest it to make some ATP. Glycolysis is the only process that occurs in the cytosol, not in mitochondria.

II. ATP production: forward

>A. Overview- so, the production of cellular "batteries" (ATP) involves 4 major processes:

-Glycolysis, which splits a glucose into 2 pyruvate, and provides a little ATP. Some H are released, picked up by NAD+, and brought to the ETC.

-Pyruvate --> Acetyl coA, in which pyruvate loses CO2. Some H are released (where do they go?).

-TCA cycle, in which acetyl joins up with oxaloacetate to become the 6-carbon citric acid. Citric acid undergoes a series of controlled reactions which ultimately release lots of H (where do they go?). TCA cycle provides a little ATP.

-Electron Transport Chain, in which NADH and FADH2 bring H to the inner mitochondrial membrane. There, the Hs are split into H+ and e-. The e- are passed among a series of proteins. The energy they release is used to establish a H+ gradient by pumping H+ across the inner membrane.

The H+ are finally allowed to rush down their gradient through ATP synthase, an embedded enzyme located next to the last e- accepting protein. The energy released by the "rush" of H+ is used by ATP synthase to: ADP + PO4- --> ATP! A bunch of ATP gets made here.

Now, there's one more question: what happens to the e- and the H+, once they've been "used?" Right next to the last e- accepting protein is an O2. It also happens to be right next to ATP synthase, the tunnel where H+ come rushing through. Electrons get passed from this last protein to O2, which is happy to take them (O loves electrons). Now we have negatively charged Os, and we have a bunch of H+ rushing in right next to them.

The H+ and O will react and make water!

Because oxygen ultimately takes the "free" electrons and sticks them into a stable molecule (H2O), oxygen is called "the final electron acceptor."

If not enough O2 is available, the whole system, all the way to pyruvate --> acetyl coA, gets backed up. The only process that can still function is glycolysis, which can only temporarily provide enough ATP for cellular work (most cells).

>B. ATP production- some details, using glucose as our source of energy.

>>1. Glycolysis- anaerobic, occurs in the cytosol. Glycolysis requires an initial energy input to get the process started. The cell uses 2 ATP to get it going, but glycolysis will produce 4 ATP. So the cell gains 2 ATP per glucose. In addition, Hs are released and picked up by NAD+ (where will they go?). 2 NADH are generated by glycolysis.

Keep in mind that this is not a one-step process. It requires several controlled steps, each one driven by an enzyme.

>>2. Pyruvate--> Acetyl coA- this is really a transitional step and doesn't have a name. Aerobic. Once pyruvate has been produced by glycolysis, it will move into a mitochondrion. There, it will be converted to acetyl by losing a CO2. Pyruvate also loses Hs. 2 NADH are generated by this step, per glucose (how many pyruvates per glucose?).

>>3. TCA cycle- Aerobic. Generates 6 NADH and 2 FADH2 per glucose. In addition, 2 ATP per glucose are made during the TCA cycle. CO2 is also generated during the TCA cycle, which is expelled as waste.

To help you understand how atoms are rearranged along a C-backbone, how H are released, and how CO2 are expelled during this cycle, I recommend that you draw out the step Isocitric Acid --> alpha-Ketoglutaric acid. You can find the details of the TCA cycle in your Applications Manual, pg. 169. This particular step has a little bit of everything.

>>4. Electron Transport Chain- Aerobic. ~34 ATP are generated per glucose.

Now we'll shift gears a bit and talk about how specific nutrients are used for energy, or how they are made.

III. Carbohydrate Metabolism

>A. Catabolism (using carbs for energy)- See above! The breakdown of glucose for ATP is catabolism of carbs.

I will add one more detail here about glycolysis. Keep in mind that only glucose (monosachharides) can be used in glycolysis. Glycolysis is the fastest way to generate ATP. So, if cells suddenly need lots of ATP at once, it has to rely on glycolysis initially. Aerobic respiration takes a while to crank up and start producing enough ATP.

Muscle cells often have to suddenly start producing more ATP. When you start lifting weights, or moving furniture, etc., your demand for ATP rises immediately. Muscle cells split thousands of glucose all at once, generating tons of pyruvate. So many pyruvate, in fact, that they can't all get into the mitochondria.

So pyruvate get backed up in the cytosol, taking up space and not really doing anything. But we know that there's still a lot of potential energy in each one. Pyruvate can't cross cell membranes, so they are converted to lactate (lactic acid) which can cross cell membranes. Lactic acid leaves the cell and enters the blood (making your muscles burn). Lactic acid is very similar to pyruvate, it also has 3 carbons. When lactic acid reaches liver cells, they will combine every 2 lactic acids to make another glucose! Glucose may be released into the blood for use.

In this way, muscle cells can "share" the energy they can't use at the time.

>B. Making, storing, and releasing glucose- remember that most cells of the body can use glucose or fatty acids for energy, but the CNS cannot use fatty acids.

>>1. Gluconeogenesis ("new glucose rising")- This word describes making glucose from non-carbohydrate sources. Why would your body want to make glucose? Glucose can be made by many substances that have 3 or more carbons, for example: pyruvate, lactate, glycogen, many amino acids. But, acetyl only contains two carbons and cannot be used (directly) to make glucose.

>>2. Glycogenesis- making glycogen from glucose. Glycogen is how glucose is stored, most in the liver and muscles (only the liver shares its glucose, though, the muscles keep theirs for themselves). The kidneys also have a bit, and other body cells can store a little bit for themselves as well.

>>3. Glycogenolysis- breaking down glycogen to release glucose. The liver does this in response to glucagon. Muscle cells do it when they need ATP fast.

IV. Lipid Metabolism
>A. Catabolism: using lipids for ATP (lipolysis). Of the lipid classes, triglycerides are the ones primarily used for energy.

Triglycerides are split into 3 fatty acids and glycerol. The glycerol is converted to pyruvate, and can be used to make glucose or just enter ATP production as pyruvate.

Fatty acids enter mitochondria and are cleaved at every 2 carbons into acetyls. This process is called beta-oxidation. Every time an acetyl is chopped off, it binds coA, and they move to the TCA cycle. During beta-oxidation, some Hs are released (where do they go?)

Since fatty acids have varying chain lengths, each fatty acid can be chopped into a different number of acetyl coAs. For example, how many acetyl coAs can you get out of oleic acid, with 18 carbons? Butyric acid, with 4 carbons? Since fatty acids produce different numbers of acetyl coAs based on their chain lengths, the amount of ATP from fatty acids varies. For example, between the acetyl coAs and NADHs generated during beta-oxidation, an 18- carbon chain will produce 144 ATPs. Considering how lightweight they are, this points out why they make great storage molecules!

Ketone bodies

When lots of fatty acids are being used to make ATP (like if you're on a very low-carb diet, or are diabetic), cells generate TONS of acetyls. So many, in fact, that there aren't enough oxaloacetates to bind with them and take them into the TCA cycle. So, the acetyls start backing up, not doing much of anything.

We know the acetyls still have lots of potential energy, which other cells could use. However, Acetyl coA can't leave the cell. So, acetyls are converted to ketone bodies, which can leave the cell. Ketone bodies can be used by virtually all cells (including most CNS) for energy.

Two of the three ketone bodies are acids. The other one is acetone! Ketone bodies that aren't used by cells are excreted by the kidneys and exhaled. If a person produces so many ketone bodies that they can't be excreted fast enough, blood pH will drop and that person could enter ketoacidosis, when pH drops below a functional range. This is a concern primarily for diabetics.

Ketone body production is normal, and is an important adaptation for dealing with starvation.

>>B. Anabolism- lipid synthesis (lipogenesis)

Glycerol can be made from glucose and pyruvate.

Fatty acids are made by attaching acetyls together. Therefore, anything that can be reduced to acetyls can be used to build fatty acids.

There are 2 fatty acid classes we can't make: Omega 3 (including linolenic acid) and Omega 6 (including linoleic acid). These are called "essential," because we need them from our diets. They are precursors to the prostaglandins cells use as local hormones, and are important components of phospholipids.

>>C. Lipid Transport and Distribution- how fats get around (generally in phospholipids, which allow them to travel in the blood without blobbing up). Phospholipids are named based on their relative density. The largest phospholipids are the LEAST DENSE, because they have the most lipid in relation to protein. Lipid is not dense, protein is very dense.

>>>1. Remember chylomicrons? Largest and least dense. Again, these will travel through the lyphatic system before getting to the blood. Once they get to the blood they will deliver mostly triG to cells in need. When they reach the liver, the liver will break them down and repackage them into one of the following.

>>>2. Very Low Density Lipoprotein (VLDL)- smaller and more dense than chylos. The liver packages them and releases them to the blood. Their purpose is very similar to chylos.

>>>3. Low Density Lipoprotein (LDL)- smaller and more dense than VLDL. The liver packages them and releases them to the blood. LDLs deliver cholesterol to cells in need. Why would cells need cholesterol?

The thing is, LDLs enter cells via endocytosis. Inside the cell, an LDL is completely broken down. The cell takes the cholesterol it needs, then dumps the rest out free in the blood, so we end up with a blob of cholesterol in the blood (which will attract more lipids).

The other thing is, WBC attack old LDLs and dump cholesterol free into the blood, which blobs up and attracts more lipid.

Blobbed lipids tend to block vessels.

>>>4. High Density Lipoprotein (HDL)- smallest and most dense lipoprotein. These are packaged by the liver and sent out to the blood. They go around and sweep up loose cholesterol. So, the more HDLs you have, the faster and better loose cholesterol gets cleaned out.

HDLs return cholesterol to the liver, which can use them to make new LDLs, or make bile salts out of them.

Fiber intake can help reduce cholesterol because in the digestive tract, fiber binds cholesterol. We know that fiber ends up going out (we can't digest or absorb it), so it drags cholesterol out with it. So, bile salts get pulled out by fiber, and the liver has to take some cholesterol out of circulation to make new bile salts.

V. Protein Metabolism

>A. Amino acid catabolism (using a.a. for energy)- in order to be used for energy (or any non-protein use, for that matter), amino acids must have their amino groups (NH2) removed: deamination. When NH2 is removed, it will immediately bind one or two H+, producing ammonia (NH3).

Ammonia is toxic. Liver cells contain an enzyme that detoxifies ammonia by combining 2 NH3 with a CO2, producing urea. Urea is much less toxic than ammonia. Urea is released to the blood, where it will be filtered by kidneys and excreted in urine.

Now, the amino acid has been deaminated and we are left with a carbon backbone. Since each of the amino acids has a different C-backbone, each amino acid has a different fate, in terms of how it can be used to make ATP. Some can be converted to pyruvate, some to glucose, some to acetyl, and some to intermediates in the TCA cycle (so they just jump right in the middle of the cycle).

>B. Anabolism- amino acid synthesis

We can easily make 10 of the 20 amino acids. The others are considered essential because they must be provided by the diet.

To make an amino acid, a liver cell first builds the carbon backbone of the amino acid it needs. Then, it swipes an amino group from another amino acid: transamination.

VI. Metabolic Interactions- What's happening with nutrients in the body, when, where and why. Keep in mind that liver cells store glycogen, make glucose, and send fats out en masse. Muscle cells store glycogen. Adipose cells store triglycerides, which they can release when needed.

Absorptive State- up to ~4 hours after a meal, a time when nutrients are entering the blood, are plentiful and being stored. The primary hormone is insulin.

PostAbsorptive State- ~4 hours or more after a meal, a time when stored nutrients are released to the blood. The primary hormones are glucagon, cortisol, and epinephrine.

Cell type	Absorptive State	PostAbsorptive
hepatocytes	use glucose for energy, store glucose as glycogen	use fatty acids for energy, release ketone bodies to blood, release glucose to blood from glycogen
skeletal muscle	use fatty acids for energy (resting), store glucose as glycogen	use glucose for energy to create lactic acid to share with other cells
adipose	use glucose for energy, store fatty acids	use fatty acids for energy, release fatty acids to blood
most cells	use glucose for energy	use fatty acids and ketone bodies for energy
neurons	use glucose for energy	use glucose and ketone bodies for energy

 

 

 

ANP 214 Main Page