Structural Biochemistry/Vitamin C

Introduction

Vitamin C known as the anti-scurvy vitamin was discovered by scientists. Some even called it the hexuronic acid or ascorbic acid. This vitamin can be used to treat scurvy. For those who don't know, scurvy is a disease caused by the lack of vitamin C; as a result, it can cause opening of past healed wounds and cause the gums to be swollen or even bleed. Scurvy can also cause vision problems, lassitude, haemorrhages, bone fragility and neurological problems.

Scurvy

Doctors recommend us to digest more vitamin C for our body through the intake of fruits and vegetables. But sometimes that might not be enough of vitamin C to compensate the amount that we lack in the body. Chemically, scurvy happens because of the inactivation of some important dioxygenases. These enzymes are dependent on the ascorbic acid and are part of the class of 2-oxoglutarate dependent dioxygenases (2-ODDs). The mechanism of this enzyme requires Fe²⁺ , 2-oxoglutarate ,and ASC as co-substrates to get the process going. Overall, 2-ODDS would convert O₂ into organic substrate.

The ASC mechanism

Each 2-ODDS will have its own responsibility in the mechanism. As a result, some 2-ODDS would catalyze the hydroxylation, while some would run the desaturation and ring closure or expansion. Scurvy, a disease, that can be treated using this ascorbic acid.And scientists usually call this process as the ASC administration. Its role is to keep the Fe²⁺ constant. The mechanism of the peptidyl-prolyl- 4-hydroxylase (P4H)uses the enzyme for the pre-translational hydroxylation at the 4th Carbon of the proline residues that was inside the polypeptide chain. So this enzyme would split the oxygen into organic substrates such that they can be used in the decarboxylation of 2-oxoglutarate and oxidation of proline.The ASC is used to become another acceptor of the Fe²⁺ ion mechanism, so it can drive the mechanism without the need of hydroxylation. Because the mechanism of the ferry ion is complicated and very reaction, the ASC and the 2-ODDS might have to undergo the molecular co-evolution in order to carry out the reaction. When there's a lack of ASC in the body, it would result in the inactivation of the P4H and lead to the scurvy disease. Hence, the collagen residues would not be hydroxylated and the collagen trimers would not form. Specifically, it's required to carry out the hydroxylation of the proline to make sure that the collagen would fold. As a result, the folding of collagen would form into the triple helices and then into fibrils that can help with thermal stability. These collagen folding help to maintain the skin, tendons, cartilage, bones, teeth, cornea, muscles, and blood vessels. So it's very important that this process occur. Scientists have discovered the relationship between the lack of ASC to the non-folding problem of collage. For instance, they realized that guinea pigs with free ASC diet have lower amount of type IV collagen and that results in the lower amount of hydroxylated proline. As a result, the guinea pigs experience scurvy which leads to the defects in blood vessels. Since collage consumes a large amount of ASC and lack of ASC can lead to scurvy, we can conclude that the non-folding of collagen plays important role in scurvy.

Another role of Vitamin C

Another group of dioxygenases that depend on ASC can drive the repair of methylated bases in DNA sequences. And other ASC dependent plant-dioxygenases can help to synthesize hormones of the signaling molecules such as gibberellins and ethylene.

HIF Hydroxylation Signaling

ASC plays an important role in HIF hydroxylation signaling. HIF1 is known as the one of the HIF members such that it can activate hundreds of genes that are related to nutrient transport, cell migration, angiogenesis, and energy metabolism. HIF 1 has 2 subunits: α and β subunits. Scientists have discovered that the mechanism that is catalyzed by dioxygenases need to include oxygen. And what drives the mechanism with oxygen is the hydroxylation of 2 proline residues. There are two proline residues in humans. They are Pro402 and Pro564 which are parts of the HIF-α. They are hydroxylated by 3 different hydroxylases (HIF-P4H) and they carry the same processes as the collagen hydroxylases. However, there are differences between the collagen hydroxylases and HIF-P4H. HIF-P4H can be found in the cytosol, while collagen hydroxylases are found in the ER. In HIF-P4H, the affinity of the enzyme for O₂substrate or the K_m value for O₂ is above the atmosphere concentration which means that they can identify oxygen in the mechanism. When oxygen is available, we call that the normoxic conditions. In that condition, the 2 proline residues would be hydroxylated. Then it results in the binding of the multiprotein complex in order to attack the protein pVHL and the degration of HIFα. The condition of the mechanism with lower oxygen is called the hypoxia, while the condition with no oxygen availability is called the anoxia. And when these conditions occur, hydroxylation cannot happen. As a result, HIFα would not be attached to the protein pVHL and result in the binding of the HIFα and the HIFβ in the nucleus. The presence of oxygen can be used to activate the hydroxylation in the mechanism, and its presence can make ASC's presence to be less important in the reaction. Scientists have discovered that in the normoxic and hypoxic conditions, ASC plays an important role. ASC helps to lower the amount of HIF1 protein while icreasing the rate of degration of HIFα. When one adds ASC to the reaction, it may help to increase HIF hydroxylation in deficient cells. Another study shows that lowering the ASC concentration can result in lowering the hydroxylation rate of HIFα and that can result in the lowering the rate of degration of such protein. Overall, ASC play multiple roles such as it would activate the enzyme by decreasing the amount of Fe³⁺ and it can bind to the enzyme while acting as a substrate

Cancer treatment

Scientists have done different experiments on ASC's role in treating cancer. They discovered that increasing the concentration of ASC can cause the HIF down-regulation. Since HIF1α is expressed in the treatment of cancer, there has been experiments show the lack of ASC is expressed in cancer patients. Scientists have been working on how the function of ASC can help with the immune cells in the patients' body.\

Gene expression

ASC has played multiple roles in expressing genes. Studies show that vitamin C can help with the gene transcription process such that it can stabilize the mRNA. For example, the transcription of the tyrosin hydroxylase was catalyzed by vitamin C. In addition, ASC can differentiate the members of the mesenchymal cell by making more collagen. And the members of the mesenchymal cell are chondrocytes, cardiomyocytes, and osteoblasts. In osteoblasts, osteocalcin, a binding protein that is made from osteoblasts, can be expressed by ASC. The process occurs when there is an increase of ASC that results in the transcription of osteocalcin genes. Also, there was a mouse model used in experiment of Charcot Marie Tooth syndrome. ASC helps to cause the myelination in the mouse such that it finds a new pathway to treat the syndrome.

Reference

Tullio, Mario C. De. Beyond the antioxidant: The double life of Vitamin C.12/6/12