Vitamin K

00:01 This lecture will focus on two of the fat soluble vitamins, vitamins K and E and two groups of molecules involved in what we call one carbon metabolism.

00:10 Vitamin B12 and another group of molecules called the folates.

00:14 Now, vitamin K is a fat soluble vitamin that plays very important roles in the blood clotting process and also, an important role in maintaining bone health.

00:25 Like the other fat soluble vitamins, vitamin K is stored in fat tissue.

00:30 It is found very abundantly in green, leafy vegetables like kale, spinach, and collards.

00:35 It's a compound that's stable in the air but it does decompose when exposed to sunlight.

00:41 There are several forms of vitamin K, including natural forms that are found in nature and manmade forms that also appear to function in a similar fashion.

00:51 Vitamin K-related modifications facilitate the binding of calcium to target proteins and this is what really vitamin K's function is in both the blood clotting process as well as in maintaining bone health.

01:05 It's the absence of vitamin K that leads to uncontrolled bleeding in an individual.

01:10 Meaning, of course, the vitamin K is essential for the clotting process.

01:14 A deficiency of vitamin K however is relatively rare in health adults and it is required for bone formation.

01:22 Vitamin K is actually a group of molecules.

01:25 Now, the form known as vitamin K1 is also known as phylloquinone.

01:29 It's an electron acceptor that's found in plants in the photosynthesis system known as photosystem I.

01:35 As I said, it's found in the green leaves and because of the chlorophyll that the plants have, this compound is quite abundant in those plants.

01:43 Vitamin K is involved in the carboxylation that is adding carboxyl group to the glutamates sidechains of the blood clotting factors.

01:51 This includes blood clotting factors II, VII, IX, and X.

01:55 Vitamin K can also be involved in the carboxylation of other compounds in the preventing of clotting process as well as some bone proteins.

02:03 So, some of the anticoagulation factors that vitamin K can carboxylate includes the glutamate sidechains of factors proteins C and S.

02:13 Now, so, we can imagine that vitamin K's role of carboxylation is a very important one and as we will see in a minute why that's the case.

02:20 So, as I said, vitamin K is a group of molecules.

02:23 Vitamin K2 is known as menaquinone and it's a group of compounds that different in the number of isoprene units that they have.

02:30 An isoprene unit is a group of carbons and hydrogens that are shown in the figure on the right, in the bracketed portion.

02:37 They actually contain five carbons and the rest being hydrogens.

02:40 The isoprene unit is the way that the molecule is built.

02:44 So, molecules that are built using this vary in how many they have and therefore, vary in their sizes according to five carbon units.

02:51 MK-4, also known as menatetrenone and MK-7 are subtypes of vitamin K2.

02:57 They are also involved in glutamate carboxylations as is K1 and they're involved at the same level as vitamin K1 is.

03:05 Vitamin K1 as I said is found in plants but bacteria take that vitamin K1 that we get in our diet and they covert vitamin K1 to vitamin K2 and another form known as MK-7 as well as MK-8, MK-9, MK-10, and MK-11.

03:22 So, you see that there are quite a variety of these vitamin K's that are present in our body.

03:27 MK-4 also known as menatetrenone can be produced by animals in their testes, pancreas, and arteries.

03:34 And it turns out, it's the only form of vitamin K2 that's actually made by animals.

03:39 So, we see the bacteria play a very important role in us being able to have the right vitamin K that we need in our body and they do this through metabolism residing in our gut.

03:50 So, these are three synthetic forms of vitamin K that you can see on the screen that are manmade but that all will also function in the capacity of vitamin K.

03:59 This includes vitamin K3, menadione, vitamin K4 is shown here, and vitamin K5, and all these appear to be pretty fairly safe with the exception of vitamin K3 which in higher doses can be toxic.

04:13 Now, vitamin K as I said is needed for the carboxylation of proteins.

04:18 So, let's take a minute to understand how that happens.

04:21 Here is the amino acid glutamate which is found within a polypeptide chain.

04:26 We can see its sidechain that contains the carboxyl group at the very top of this molecule.

04:31 Catalysis by the enzyme glutamate carboxylase using oxygen, carbon dioxide, water, and protons produces a modified form of glutamate known as gamma-carboxyglutamate.

04:44 Now, this gamma-carboxyglutamate has an extra carboxyl group that's added to it and that turns out to be critical for the function of this protein because with this added carboxyl group, the molecule can bind calcium.

04:57 Now, calcium as we've seen over and over in these lectures is very important for a variety of processes and in the blood clotting process, calcium is abundant at the place of the clot.

05:09 So, the ability of blood clotting proteins to bind to calcium helps them to remain at the site of a wound to help the clotting process to occur.

05:19 Now, the way that vitamin K fits into this scheme is vitamin K is a cofactor for the glutamate carboxylase and this cofactor allows glutamate carboxylase to do what it does.

05:33 And the reaction that's catalyzed by putting the hydroxyl group on and this is a very unusual reaction, again, using molecular oxygen, vitamin K acts as an acceptor of one of the atoms of oxygen.

05:45 So, you can see that vitamin K in this reaction is converted to an unusual molecule called vitamin K epoxide and that oxygen that vitamin K accepted from the oxygen is present in a three member triangular ring on the right side of the molecule.

06:02 In order for the vitamin K to function in the body, it has to be reconverted back to its original form by an enzyme.

06:10 If that reconversion back doesn't occur, then the body will eventually run out of vitamin K and the person will lose the ability to clot blood.

06:18 So, the recycling process of vitamin K epoxide, that oxygen containing molecule is very critical.

06:26 Recycling is essential for the body to have the clotting factors that it needs.

06:30 While the reaction that needs to happen is actually a fairly simple one, although, it's kind of odd, it involves the loss of water from vitamin K epoxide as the reaction shows that results in the reproduction of vitamin K.

06:43 This reaction is catalyzed by a very important enzyme known as vitamin K epoxide reductase.

06:49 Now, vitamin K epoxide reductase is present in normal amounts in the cells and this reaction occurs pretty routinely and you don't think about it.

06:57 Now, but there are people for example who have problems with clotting.

07:01 Those people who have problems with clotting may lose a limb, they may have problems with heart attacks or stroke, and it's known and it's fairly easy to measure a person's clotting ability, and they're called clotting tendencies that a given person's blood has.

07:15 If you're a person who has blood that tends to clot more readily or form clots more readily, your doctor may put you on what's known as a blood thinner.

07:23 And a blood thinner is a molecule that inhibits this reaction.

07:28 One of the blood thinners that's commonly used is known as warfarin or also called Coumadin.

07:33 Warfarin's also known as rat poison.

07:37 So, some of the people that you know who take blood thinning medications are actually taking a form of rat poison.

07:43 Well, they're not getting poisoned, of course, because a person who is given this as a treatment by their doctor is given it in limited doses.

07:51 So, it takes a certain amount of warfarin to reduce the clotting to a level that is acceptable.

07:57 Too much warfarin, you could imagine, will result in too little clotting and when you have too little clotting, you can die of hemorrhage.

08:04 So, getting the right level of clotting is important and warfarin can play a very important role in establishing the right level within a person.

08:13 Once a person is on warfarin, they will periodically have to go to their doctor to get tested regularly to see if their clotting tendency has changed, and then the amount of warfarin that they're given will be adjusted accordingly.

08:25 So, vitamin K, warfarin blocks vitamin K cycling as I said.

08:29 The lack of vitamin K stops protein carboxylation and that protein carboxylation is critical for the clotting process.

08:36 And low protein carboxylation can slow the blood clotting.

08:41 Vitamin K is also important for bone health.

08:45 It stimulates the carboxylation of bone proteins and activates many of them and this turns out to be important because we remember that bones are an abundant source of calcium.

08:55 Three of the proteins that vitamin K carboxylates are shown below.

08:59 The first is osteocalcin. It binds to the bone matrix and stimulates osteoblast and it does this, of course, by binding that calcium.

09:08 If it gets carboxylated by vitamin K appropriately, then that binding will occur and the bone matrix will be stimulated.

09:16 The matrix gla or GLA protein also binds calcium and it organizes bone tissue in the proper fashion.

09:25 And the last is periostin and it's involved in the cell migration during bone development and may be overexpressed in some cancers.