User:Gzorg/Vitamin B12

As this page title says, this page is about Vitamin B12. But let's first talk about...

= Cobalt =

Cobalt is a metal. It as atomic number 27. That means it has 27 protons, and more or less neutrons. It is between Iron and Nickel in the periodic table.

One of the distinguishing feature of Vitamin B12 is that it contains cobalt, and that metal is not that common in the environment. Also, metals play very special roles in the organism.

In organic chemistry, the basic chemical elements are Hydrogen, Carbon, Oxygen, and Nitrogen, which are very abundants.

Common auxiliary elements include Sodium, Magnesium, Phosphorus, Sulfur, Chlorine, Potassium, and Calcium.

Trace elements are Manganese, Iron, Cobalt itself, Nickel, Copper, Zinc, Selenium, Bromine, Molybdenum and Iodine.

The availability of Cobalt is similar to that of Potassium and Chlorine, and is less than that of Nickel and Iron.

= Pyrrole =

Vitamin B12 contains a corrin ring. That ring is a tetrapyrrole, which is made of four pyrroles. So let's talk about pyrroles first.

A pyrrole is a ring made of four carbon and one nitrogen atoms. That's a very basic structure. Obvious variations include replacing the nitrogen with either oxygen, which yields furan, or with sulfur, which yields thiophene. The hydrogen in the pyrrole is necessary because nitrogen likes to binds to three elements, while oxygen and sulfur prefer two.

= Tetrapyrroles =

Tetrapyrroles are molecules that are made of four pyrroles. It happens that these are more numerous than those made of only three pyrroles, say, or than those made of five pyrroles. These pyrroles can be spread in the molecules, such as in phycoerythrobilin, which nobody cares about.



But most interestingly, these four pyrroles can themselves been linked into cyclic molecules, such as corrin, porphyrin or chlorin.

Corrin is used to receive cobalt atoms in cobalamine. Anything that contains a corrin is a corrinoid.

Porphyrin is used to receive iron in heme.

Chlorin is used to receive magnesium in cholorophyl.

Note that the difference between porphyrin and chlorin is very small, they both have the same structure, except one double bond in the bottom left of porphyrin is a single bond in chlorin. In corrin, one carbon atom is missing and one of the cycle has no double bond, and some nitrogen are saturated with carbon-nitrogen bonds, while other have only two nitrogen-carbon bond and one nitrogen-hydrogen bond.

Also note that chlorin does not contain a single trace of chlorine. The name chlorin comes from the greek for green. That's not helpful.

Of course, since we are dealing with Vitamin B12 here, will will let porphyrin and chlorine on the side, and continue only with corrin.

= Vitamines and vitamers =

A vitamine represents a set of specific molecules, and vitamers are the member of that set. Usually, two different vitamers of a vitamine can be converted from one into another, but different vitamers usually exhibit different properties.

= Vitamin B12 =

Let's jump directly to the big Vitamin B12 vitamers. Compared to corrins and some other vitamines vitamers, Vitamin B12 vitamers are rather big, but they can still be drawn fully on a page. Some molecules are way way bigger.

Cobalamin
Vitamin B12 vitamers are also called cobalamines. The following picture is a generic representation of Vitamin B12. The generic structure of cobalamine seems relativaly alien compared to most bioorganic substance, and it seems to contain within itself many possibilities of molecular arrangements. There is the corrin ring, with the cobalt atom in the middle, and the radical R attached to the cobalt. That R radical is the sole thing that varies from one cobalamine to another. The molecule also contains seven acetamide groups, eleven methyl groups, one phosphate group, one ribofuranose group, and one benzimidazole group. Although the top of the structure exhibits some regularity, with all its acetamide and methyl, the path from the corrin to the benzimidazole is rather convoluted, since it include an acetamide, then the phosphate, then the ribofuranose. That's quite a diversity of structure for a single molecule !



Molecular groups included in Vitamin B12 are shown in the table below.

As a side note, the level of precision of the vocabulary depends on the context in biochemistry. For example, although the pyrrole is a precise molecule, chlorin is not really a tetrapyrole, because one of its pyrrole-like group is actually a pyrroline. There are actually three kinds of pyrroline, and they can be found in the table below.

Same applies to riboses. There are actually ribopyranose and ribofuranose, with various numbers of hydroxyl or hydroxymethyl groups. Nature chooses the particular combination according to its own taste, and these levels of details, although essential for complete understanding, are not necessary for the broad picture.

As an added bonus, here's what Vitamin B12 looks like in 3D



Vitamers
Vitamin B12 has four vitamers. From simples to most complicated, those are hydroxycobalamin, cyanocobalamin, methylcobalamin, and finally adenosylcobalamin. Here are each of the molecules, whith their respective radical in the bottom rows of the table.

First, it is notable that the three first variations are substitution of the the basic elements of life. Hydroxycobalamin uses oxygen, while cyanocobalamin uses nitrogene, and methylcobalamine uses carbon. Those may come with more or less hydrogen and carbon, as nature sees fit. The fourth is most interesting, because it links the cobalamin to an adenosine molecule. And where does one find adenosine ? Read along !

ADP and ATP
Energy in the body is produced in the mitochondria, which are the power plants of the cells that look like peanuts.

The process is rather involved, but the input and the output are very easy to grasp. There is one molecule that acts like a battery cell. When it goes out of the mitochondria, it is charged, and when it comes back in, it is empty. The charged version is adenosine triphosphate, or ATP, and the discharged version is adenosine diphosphate. These two molecules, along with the less useful adenosine monophosphate, are shown in the table below.

The difference between ATP and ADP is therefore really simple. ATP has three phosphates, hence its name, and ADP has two phosphates. The act of taking one phosphate out of ATP to produce ADP gives usable energy, and that's how energy circulates in the organism. To understand why it is so, of course, is not the subject of this page. End of digression.

Back to adenosylcobalamin
It is interesting to see that some adenosine, that is to say, the part of ATP or ADP without the phosphate, gets a role in vitamine B12. It is even more so when one learns that one of cobalamine's main role is played inside the mitochondria. Actually, when cobalamine enters the mitochondria, it gets some adenosine attached to it and that's how it is activated there.

Something else is very fascinating. Remember the phosphate-ribose-benzimidazole part of cobalamin that appears at the bottom of the molecule ? Do you see how it is very similar to adenosine monophosphate ? But despite being similar, it got the adenine part substitued with a benzimidazole. This surely happened in some archaic bacteria. It looks like this may be a trace of very ancien molecular processes that happened at the dawn of life, then came into disuse, or rather got very specific uses. And indeed, benzimidazole only appears in Vitamin B12.

Conclusion
Cobalamin is a very peculiar molecule indeed. It is full of history. It features remnant of archaic bacterial processes. It uses the three basic element of life in its variation. It features a metallic cage that contains a single atom of cobalt. It can be synthesized by neither animals nor plants, but only by bacteria. And yet, it is important for life, since it takes part into a key step of the citric acid cycle. But we are not there yet. No no. We are in the mouth.

= Vitamin B12 in the mouth =

When one of the Vitamin B12 vitamers enters the mouth, it can stay there, or go straight into the stomach.

If it goes in the stomach, it will be attacked by the gastric acids.

But if it stays, it may get attached to transcobalamin I, also named haptocorrin.

So, we already know the structure of cobalamines fairly well, so what is haptocorrin ? Well, it is bigger than cobalamine, so that it cannot be displayed on a page. It is a protein. It's known as 4KKI or 4KKJ in Protein Data Bank database. If you go there, you may be able to find a file that contains the following text:

MRQSHQLPLVGLLLFSFIPSQLCEICEVSEENYIRLKPLLNTMIQSNYNRGTSAVNVVLSLKLVGIQIQTLMQKMIQQIK YNVKSRLSDVSSGELALIILALGVCRNAEENLIYDYHLIDKLENKFQAEIENMEAHNGTPLTNYYQLSLDVLALCLFNGN YSTAEVVNHFTPENKNYYFGSQFSVDTGAMAVLALTCVKKSLINGQIKADEGSLKNISIYTKSLVEKILSEKKENGLIGN TFSTGEAMQALFVSSDYYNENDWNCQQTLNTVLTEISQGAFSNPNAAAQVLPALMGKTFLDINKDSSCVSASGNFNISAD EPITVTPPDSQSYISVNYSVRINETYFTNVTVLNGSVFLSVMEKAQKMNDTIFGFTMEERSWGPYITCIQGLCANNNDRT YWELLSGGEPLSQGAGSYVVRNGENLEVRWSKYLVPRGSLESRGPFEQKLISEEDLNMHTGHHHHHH

Now, this may be a bit cryptic, so in order to decipher that, one need to know about the FASTA file format. Reading that, you'll learn that each letter code for an amino acid. So, for example, the first amino acid in the sequence is a 'M' for methionine, the second is a 'R' for arginine, and so on, and so forth, and at the end, there are six histidines.

Proteins are chains of amino acids. They are synthesized by the cells. They are actually all synthesized by the same factories, which are ribosomes. These things are themselves very very complex units, made mostly of proteins and other molecular structures. That's one part of the fascinating thing, that proteins are made by things that are themselves made of proteins, that were made by... something, but what ? It's a bit like robots begin built by robots.

What is also fascinating is that these proteins are actually the product of a schematic, and that that schematic is directly encoded in the DNA.

So, now, what is the DNA ? Every know that ! DNA is made of guanine, cytosine, adenine, and thymine.

These molecular units are paired together in the famous DNA strands, as show below:



There, it can be seen that adenine pairs to thymine, and cytosine pairs to guanine. It can also be seen that each nucleotide bind to a furan on each side, and that these furan are bound together by phosphate.

DNA lives in the cell's nucleus, and ribosomes lives within the cell, but outside the nucleus. There are complicated things that control gene expression, i.e. whether some sequences of DNA are read or not. When a sequence is read, it is copied, then sent out of the cell, in the form of RNA. RNA is basically the same as DNA, but it uses uracil instead of thymine. Things are possibly a bit more complicated than that.

But then RNA, or something similar, comes into contact with the ribosomes, and the ribosomes start reading it. The very interesting fact is that this process is simple, incredible, and well understood. Each sequence of three nucleotide is associated to one amino acid. The ribosome start reading the sequence, and then, depending on what it reads, it decides to chain some amino acid or another. So that's mean that there is a gene that control the expression of haptocorrin in the mouth, and not somewhere else in the body. When the body decides that haptocorrin is needed, gene production is turned on, and ribosomes start producing it. And then, what gets out is the aforementionned sequence of amino acids.

So, given that nucleotides are read by group of three, and given that there are four nucleotides, how many amino acids are possible ? That's sixty four. But for some reasons, nature decided that less amino acids were necessary, but that sixteen were not enough, so there are twenty one amino acids, and they are given in the following table. That's very convenient, because there are twenty six letters in the alphabet, so we may use one letter for each amino acid. I'm sure that five letters in the alphabet are useless. For example, why do we keep using 'Q' and 'Z' ? I'm sure we could get rid of those.

The most notable things about amino acid is that they all contain an acetamide group. It's very useful to have something common to produce chains out of elements. The rest is mostly unique. Cysteine and methionine both contain sulfur, and Selenocysteine contains selenium. So sulfur and selenium in the diet is possibly important.

Just fire up Youtube to see many beautiful animations of ribosomes at work. That's really cool, it's like Lego.

Haptocorrin bound to cobalamin
So, that's was a nice summary of what proteins are and how they are made, but how does haptocorrin binds to cobalamin and how does it prevent cobalamin from being attacked by gastric acids ? Well, that's difficult.

The most fascinating thing about proteins is that these various sequences of amino acids fold in different ways. And that difficult-to-predict folding gives them their function. Actually, the folding varies with the pH of the environment, so that proteins will act differently at different pH. That makes it even more difficult to study, and what comes out is that haptocorrin binds to the acid-sensitive part of cobalamin, so that it's protected.

The figure below represents a three dimensional rendering of haptocorrin. It is made of two parts, with a small link binding them together. The green, yellow, blue, orange and red parts are all part of the same long chain of amino acids. When this thing meet a cobalamin, it binds to it and keep it. Something has to come after to break the thing apart, and free the cobalamin from the haptocorrin. The fact that the particular sequence of amino acids chose to fold itself in that very specific way is one of the wonder of nature.



= Vitamine B12 in the stomach =

Welcome in the stomach. This environment is very acid, because the parietal cells of the stomach produce hydrochloric acid, which is one of the strongest acids on Earth. Fortunately, you Vitamin B12 is well protected in haptocorrin.

The parietal cells also produce intrinsic factor. Intrinsic factor is also protein, therefore, it is also a sequence of amino acids and it is also coded by a gene, whose name is 'GIF'. Its FASTA is the following, it's about the same size as haptocorrin.

MAWFALYLLSLLWATAGTSTQTQSSCSVPSAQEPLVNGIQVLMENSVTSSAYPNPSILIAMNLAGAYNLK AQKLLTYQLMSSDNNDLTIGQLGLTIMALTSSCRDPGDKVSILQRQMENWAPSSPNAEASAFYGPSLAIL ALCQKNSEATLPIAVRFAKTLLANSSPFNVDTGAMATLALTCMYNKIPVGSEEGYRSLFGQVLKDIVEKI SMKIKDNGIIGDIYSTGLAMQALSVTPEPSKKEWNCKKTTDMILNEIKQGKFHNPMSIAQILPSLKGKTY LDVPQVTCSPDHEVQPTLPSNPGPGPTSASNITVIYTINNQLRGVELLFNETINVSVKSGSVLLVVLEEA QRKNPMFKFETTMTSWGLVVSSINNIAENVNHKTYWQFLSGVTPLNEGVADYIPFNHEHITANFTQY

So, what is there to say here, not much. In acidic environment, intrisinsic factor does not bind very well to cobalamin. So we can no leave the stomach into the duodenum and small intestine.

= Vitamin B12 in the duodenum/small intestine =

When cobalamin enters the duodenum, then the small intestine, it is expected to be bound to haptocorrin. And intrinsic factor must bind to it, but it can't. So, there's something that comes and destroys the haptocorrin that is no more needed. Although it is believed that the things that do that are enzymes produced by the pancreas, which one it is is not known. So, well, there's something that frees the cobalamin from haptocorrin, and the intrinsic factor binds to it.

An enzyme by the way, is usually also a protein. But these proteins have special abilities, such as being able to take something and breaking it into specific parts, or combining different things together, or something.

Once cobalamin is bound to intrinsic factor, it can enters the enterocyte. Cobalamin cannot cross the enterocytes by itself, it has to have the persmission of the organism. Isn't this marvelous ?