FUNdamentals

Dr. Miller

8/29/08 11:00 – 12:00

Slide 1 - METABOLISM - BASIC CONCEPTS

  • We are going talk about a lot of reactions.
  • Looking at anabolic and catabolic processes that satisfy the metabolic needs of the cell of the organism.
  • Vast array of reactions that you have to get used to, but there is a common theme among the reactions. There is a set of biochemical reactions that encompass everything. There may be deviations from that theme, but if you find a common motif, then you will see the coherency of the design.
  • There are relatively a small number of types of reactions.

Slide 2 – Diagram: Energy Flow

  • Solar energy drives all energy.
  • Photoautotrophic cells synthesize glucose and give off oxygen.
  • We are heterotrophic organisms, so we take the glucose and oxygen and we convert it to carbon dioxide and water, which feeds the plants and the cycle continues.
  • Of course carbon dioxide is the “bad boy” of the atmosphere.
  • If you don’t like carbon dioxide, quit breathing =)

Slide 3 - CATABOLISM AND ANABOLISM

  • Metabolism consists of catabolism and anabolism.
  • In Anabolism you are using the energy as you build new molecules.
  • Catabolism is a degradative pathway, usually energy-yielding.
  • Some of the energy we take in and store, and we will reutilize for making new molecules by synthesizing proteins.

Slide 4 –Diagram: Catabolic vs. Anabolic Energy

  • This shows you energy yielding nutrients: carbohydrates, proteins and fats.
  • Go to low energy products (H2O, CO2 & NH3)
  • On the other side, we have precursor molecules like amino acids and sugars, etc., which we will anabolize and convert them back to proteins, polysaccharides, etc.
  • The kinds of substance we don’t’ get on one side we make for ourselves on the other side.
  • A lot of enthalpy here

Slide 5 - Organization in Pathways

  • Skipped

Slide 6 – Diagram: Multienzyme pathways

  • Pathways can be organized in a variety of ways.
  • Basically what that means is that you can have a substrate going to a product and in order to do this it must have contact with four, five or six different enzyme systems before you get your product.
  • Also times that the enzymes are organized in a way that the substance and product are not separated and can be modified rather quickly and they cluster.
  • You will have enzymes that are set up in the membrane in a situation like this (see diagram).
  • These are just an example in the variety of ways a substance can be made.

Slide 7 – Diagram: Three Stages of Catabolism

  • This is one of the examples I was talking about: common themes
  • We have proteins, carbohydrates and lipids here and these are the three major foodstuffs.
  • All of them are going to give products that come down to Pyruvate and Acetyl CoA (depicted on slide)
  • It doesn’t matter whether it is carbohydrates, lipids or proteins, you will wind up at these two products.
  • Ultimately, everything has to pass through the Acetyl CoA terminal and then into the Citric Acid Cycle.
  • This cycle is going to release carbon dioxide and then oxidative phosphorylation will come down to water.
  • The only other by-product of our metabolic activity will be ammonium which comes from the proteins, and that is made and given off in a particular channel.
  • Ultimately, NH3, CO2 and H2O are the major products.
  • This is something you need to get a hold of the idea that no matter what is going on in metabolism you will go down to Acetyl CoA and Pyruvate (3-carbon and 2-carbon type substrates).
  • There is a tremendous amount of order in this!

Slide 8 - Comparing Pathways

  • Anabolic and catabolic processes give rise to the same product using the same substances, but the steps that one using going down and up in these processes often times differ.
  • Sometimes they are common, but there are a variety of ways in which that reversal can occur.

Slide 9 – Diagram: Regulating Pathways

  • For instance, you can have substance A going to a product by a totally different enzyme system that was used from going from the product back to the original substance.
  • This is one set of enzymes, and this is another (note slide)
  • Notice the stopping points in the pathway in which the pathway is shut off
  • These are totally different ways (left side of diagram)
  • The other situation (right side of diagram), that we will soon see in glycolysis and gluconeogeneisis, is that part of the pathway is common from going from substance A to product and then product goes back to substance A.
  • The opposite side (anabolic side) is used and you go all the way up the same ladder, except you deviate from the circular pathway.
  • You come back through the same material.
  • There has to be a method for discrimination against one of the sides (catabolism vs. anabolism sides)
  • For rampant mutilization, you need to have a way to separate the two operations.

Slide 10 - ATP Serves in a Cellular Energy Cycle

  • Skipped because info has been covered somewhat already

Slide 11 – Diagram: ATP Cycle

  • Just pointed out diagram

Slide 12 - CENTRAL ROLE OF ATP

  • This is something that is astounding (follow slide carefully here, it gets confusing)
  • The average human consumes:
  • 42 kg ATP/24 hr
  • 42,000gm @ 507 gm/mole
  • 83 moles of ATP/day
  • 83 moles x 12 kcal/mole = 996 kcal (996 Cal)
  • Calories (capital “C”) are for nutritional purposed
  • Just divide scientific calories by 1,000 to get Calories
  • 996 calories a day we utilize on average
  • An average person is supposed to have a diet of about 2,000 Calories per day.
  • You only really need 996, where does the other calories go?
  • The heat that you radiate. You are donating some of your energy to the atmosphere and universe throughout the day.
  • We are inefficient machines, we only used about half the energy we take in…we are only as efficient as the motor in our car (car analogy followed)
  • Total body content of ATP is about 50 grams. In other words, you only have at any given time about 50 grams of ATP, which is about 1/10 of a mole of ATP.
  • The turnover times per day has to be 83 moles, which would require 830 times the amount of ATP that you have.
  • The turnover time (considering you have to do it 830 a day), you have 830 seconds in a day and divide that into 86,400 every 104 seconds you replenish all of the ATP that you have.
  • What do we use all that ATP for? Think of the billions of cells that we have that have to keep sodium and phosphate up in the membrane of a cell. Every cell is working extremely hard to utilize ATP to keep that gradient high.
  • Every minute and 44 seconds the total body content of ATP is replenished. This is why you can’t live too long without some type of metabolic activity. If you stop that activity, then the ballgame is over. You have essentially no energy for conducting these necessary processes

Slide 13 - What Food Substances Form the Basis of Human Nutrition?

  • Proteins is a rich source of nitrogen.
  • Carbohydrates provide needed energy and essential components for nucleotides and nucleic acids.
  • Lipids provide essential fatty acids that are key components of membrane as well as some signal molecules
  • (Microphone starts messing up and take a short break)

Slide 14 - ORIGIN OF CALORIES

  • Carbohydrates (e.g. glucose):
  • Molecular weight of 180
  • Standard free energy -686 calories per mole
  • Kilocals per gram of glucose is 3.81
  • Lipid (e.g. palmitatic acid)
  • Molecular weight of 256
  • Standard free energy is -2380 kcal per gram
  • (Dr. Miller used a diff unit than discussed in carbohydrates)
  • Kilocals per gram of 9.30
  • Protein (e.g. amino acid Glycine)
  • Molecule weight of 75
  • Standard free energy of -234 kcal per mole
  • (Again, a different unit....????)
  • Kilocals per gram of 3.12
  • That is the basic reason why lipid is so rich in calories.
  • The calorie differential is due to difference in reducing potential or differences in the ability to yield hydrogen for the various nutrients. In other words, the more capacity a substance has for reducing (the more tendency/ability to relieve itself of hydrogen atoms and give hydrogen atoms away) the more calories it has
  • Justification for lipid as our energy reservoir. All of us carry around lipids. The reason for that is our way of having a reservoir of energy.
  • Lipid is much more efficient that carbohydrates for energy reservoirs

Slide 15 – Diagram: State of Reduction of Carbon Atoms

  • This comes down to a little organic chemistry
  • If you have a long-chain carbon, like a hydrocarbon, you can oxidize that hydrocarbon and have a double bond.
  • You can hydrate that double bond and get a alcohol, then you could oxidize the alcohol to a ketone, and then you would have two more electrons and two more protons to get rid of.
  • So it you start with a long chain fatty acid, you can go down the line and every time you take away two hydrogens to make a double bond, you can get more hydrogens by hydrating and oxidating at the end.
  • On down the line, carbon dioxide will not allow you to get any more hydrogens
  • The higher amount of long chain hydrocarbons you have the more calories you can get because of the more hydrogen that you can get out.
  • Carbohydrate is already oxidized quite a bit…every carbon atom along the precursor molecule already has an oxygen in it.
  • Amino acids are not very good hydrogen donators

Slide 16 - Redox in Metabolism

  • What do we do with the molecules that we get?
  • We collect the protons and the electrons (hydrogen atoms) and we use them.
  • NAD+ collects electrons for metabolism and they are released in catabolism which is oxidative…substrates lose reducing equivalents, hydrogen atoms
  • In Anabolism, they receive back the hydrogen atoms….hydrogen atoms are added back to substances to make them take hydrogen away to use them for energy purposes.

Slide 17 – Diagram: Hydrogen and Electron Release

  • This is a picture of NAD+ (nicotinamide adenine dinucleotide)
  • It’s a nicotinamide because this is nicatimic acid aminated
  • Notice the adenine (which is a dinucleotide)
  • This pyridine ring accepts the hydrogen and electrons…it accepts one hydrogen and two electrons and another hydrogen is to be made.
  • Ethyl alcohol is oxidized to acetaldehyde, then where the two electrons and protons go…one proton and two electrons go here, one proton goes to the environment.
  • Right away you can see why metabolic activity produces acid because we don’t have a place for all the protons to go. Some float off into the environment.
  • Notice a reduced pyridine ring.
  • NAD+ is a major carrier when it becomes NADH of two electrons and one proton that is derived from metabolizing these various substances. That is one way we preserve some of the energy given off by our foodstuffs.
  • We take the protons and electrons and put them on substances like NADH.

Slide 18 – Diagram: NADPH Cycle

  • NAD+ also has another form in which this particular hydroxyl group is phosphorylated—NADP+.
  • NADP+ goes go to NADPH because it can take up a proton and two electrons as well, but NADP+ when it picks up a proton and two electrons is designed to use its electrons in biosynthetic reactions.
  • So, the reduced fuel is catabolized to give you the oxidized product, NADP+ picks up the electrons and protons and then utilizes them to take and reduce something else to make a product whereas NAD+ uses its proton and electrons to go onto the carboxylic acid cycle and oxidative phosphorylation.
  • This is the way to go back to using NADP+ to actually have something that you can use in the biosynthetic direction, whereas NAD+ protonated with electrons and protons will actually go to the oxidative phosphorylation for energy (ATP) production.

Slide 19 – Diagram: Compartmentalization

  • There is a compartmentalization of metabolic processes.
  • Glucose is going to be metabolized in glycolysis (uses pyruvate) and this will occur in the cytosol.
  • Pyruvate will be transported to the mitochondria for the Citric acid cycle and oxidative phosphorylation, which leads to the production of water (with assistance from oxygen) and carbon dioxide (comes from the TCA cycle).
  • That particular process is something that we will go over in the next few days. Glycolysis on Tuesday, then TCA cycle. Wednesday we will do oxidative phosphorylation.

Slide 20 – Complexity

  • Glucose utilization: the brain weight about 1400 grams (3 lbs.) and has about 108 cells and uses 120 grams (2/3 mole) of glucose per day.
  • If you do the calculations that one brain cell uses 4.7 x 1010 molecules of glucose per cell per second.
  • Your brain is a very active organ. It is the most highly metabolically active organ in the body. It does everything!
  • It has only about 3-4% of your body weight, but it consumes about half of the energy that you use everyday (it is like the U.S. in that manner).
  • One of the things that we are going to talk about is that the brain uses glucose and if no glucose is there the body will take certain measures to break down glucose in order for the brain to have glucose. This is essentially a state of starvation.

Slide 21 - PRACTICAL CONSIDERATIONS

  • You have ingested 10 macadamia nuts. Each is essentially pure lipid and each weigh 2.0 gm. At 9 Cal/gm, you have ingested 180 Cal. You feel guilty about this and wish to calculate the amount of exercise required to lose the calories. How long must you jog at a power level of 400 W?
  • 1 W (measure of rate of energy used) = 1.0J/s = 0.239 cal/sec
  • 400 W (good rate of speed) = 95.6 cal/sec
  • = .0956 Cal (nutritional calories)/sec
  • 180 Cal/.0956 Cal/sec = 1882 sec (31.3 minutes)
  • Sitting in here right now, you are running at about 50-60 W. You’re operating at a level of energy equivalent to a 60 W bulb. But your energy is spread out over a larger area. That is why you are not as hot as a light bulb.
  • Increasing the rate would allow more calories to be burned, but 180 just isn’t a lot of calories for half an hours work.
  • A little chemical knowledge allows you to calculate how hard you have to run in order to burn a certain number of calories. Machines at the recreation center will do this for you based upon watts and your weight.

Slide 22 - Special Focus: Vitamins

  • The main metabolic processes use as many as 5 different vitamins.
  • Your book has an excellent section on vitamins.

Slide 23 - Vitamins

  • This list covers many of the next slides in an overall fashion.

Water Soluble Vitamins – those which you need every day because you can solubilize them quite rapidly, and excrete them. You lose some of these every day and you take some in every day.

  • Thiamine (TPP) – Vitamin B1
  • This was the answer to this mornings quiz
  • Without a thiamine, you cannot have oxidative metabolism
  • It is the cofactor in a transformation of pyruvate to a molecule that can be used in TCA cycle and ultimately in oxidative phosphorylation.
  • In order to have aerobic metabolism, you need this vitamin.
  • Read the books section on this vitamin…and others.
  • Riboflavin (FAD) – Vitamin B2
  • Another molecule of three separate rings that takes up hydrogen and electrons (just like NAD).
  • Another electron and proton carrier.
  • Niacin – Vitamin B3
  • Likewise a component of the active enzyme system which is necessary to get pyruvate into the TCA cycle.
  • Used to be called nicotinic acid, but was changed to niacin because o
  • Component of NAD+ (electron and proton carrier)
  • Lipoic acid
  • An acyl carrier in dehydrogenase reactions
  • Also used in order to pyruvate into the TCA cycle
  • Can be an acetyl group
  • Can be any kind of chain of a carboxyl group that has lost is hydrogen
  • Pyridoxine – Vitamin B6
  • Essential for amino acid metabolism
  • It will be talked about at great lengths with Dr. Baggott
  • Pantothenic acid – Vitamin B5
  • A small compound which is used to make up coenzyme A which:
  • Functions as an acyl group carrier
  • Ushers molecules into the TCA cycle
  • Doesn’t prepare them, but just takes them into
  • Biotin
  • Prosthetic group used for carboxylation reactions
  • If you are going to toss carboxyl groups around involved in various reactions, then you are going to link them to biotin
  • Folic acid
  • One carbon donor used to pass methyl groups around
  • Most of the methyl groups come from the side chain of Methionine, which has the unusual sulfur in its side chain.
  • One carbon donor in biosynthesis reactions
  • Cobalamine – Vitamin B12
  • Very rare molecule
  • Essential for metabolism of branch chain fatty acids
  • Has an atom of cobalt in it (hence the name)
  • We can store a lot of cobalamine, but the only source is from red meat
  • Can get it otherwise from dietary supplements if red meat is not in your regular diet…this can be a problem, but should not
  • Ascorbic acid – Vitamin C
  • Essential for hydroxylation of prolyl and lysyl residues in collagen chains
  • Remember when Vitamin C was treated with anti-viral implications? There actually seems to be some value in this concept. It doesn’t make sense, but operationally it has some value.

Fat Soluble Vitamins –

  • Vitamin A (retinol, retinal)
  • There is two forms of vitamin A
  • Retinal: where the vitamin ends in an aldehyde group
  • Vitamin A retinal is a protein in the cones of the eye (in the retina) that allows us to detect photons. When it is impinged upon by a photon changes conformation because of the protein rhodopsin, which sends a signal to the brain that is has detected something (not see something…they eye doesn’t actually see anything)
  • Using all those glucose molecules the brain sorts out these signals
  • Retinol: where the vitamin ends in a hydroxyl group
  • Used for maintenance of healthy epithelial tissues
  • Vitamin D
  • Most important
  • Vitamin that allows the GI tract to absorb calcium
  • Formation of calcified structures/tissues (bone, dentin, enamel, etc.) are allowed to develop
  • The amount of vitamin D needs to be resorbed per day is large in order to keep the amount of calcium in the body high
  • Vitamin E
  • proposed reducing agent (a lot of skepticism surrounding this idea)
  • (Dr. Miller said a couple of things about this, but the microphone was mumbled and it wasn’t clear what he said)
  • Vitamin K
  • Responsible for carboxylation of specific glutamyl residues in proteins of the clotting cascade. In other words, if you need to form a clot, you must have vitamin K in order to carboxylate thrombin. Fibrin will precipitate and form a clot.
  • Sometimes inhibited by antibody agents. You can treat this, but you don’t’ want to completely prevent the formation of clots.

Things get out of control here…Dr. Miller was trucking through these slides. Sorry. Study at your own risk. Most of it was a guessing game.