IRON

Q1: How the vitamin K2 is synthesized? And what is the role of O2 and HO
formation in colorectal cancer?

Endogenous menaquinones (vitamin K2) are synthesized primarily by the bile acid-
tolerant Bacteroides fragilis strains and are present in relatively high
concentrations in the human gastrointestinal tract. A diet high in fat increases bile
secretion and production of the co-mutagenic and co-carcinogenic secondary bile
acids by the colon microflora. We have proposed that bile-tolerant Bacteroides
strains synthesize menaquinones and that vitamin K1 is a cofactor in the
dehydrogenation of bile acid substrates to yield reduced vitamins K (KH2).
Reduced vitamins can be transported into the mature colonocytes in the form of
mixed micelles to trigger formation of the superoxide radical anion and further
redox-cycling reactions forming a variety of free radicals including hydroxyl
radicals.
Redox cycling of K vitamins:

The consequence of O2 and HO formation may reflect the fact that these highly
reactive species can initiate DNA damage and hence act as initiators and promoters
of colorectal cancer. The formation of hydroxyl radicals in the colon is supported
by experiments with 1/10,000 diluted feces in which hydroxyl radicals have been
detected using DMSO as a molecular probe.
KSQ + O2 KSQ + O2
O2 + Fe (III) O2 + Fe (II)
KSQ + Fe (III) KSQ + Fe (II)
2O2 + 2H+ H2O2 + O2
Fe (II) + H2O2 Fe (III) + OH + HO
Based on the above discussion, we can conclude that a high intake of red meat
increases stool iron and bile pigments can promote Fenton chemistry and the
formation of damaging hydroxyl radicals, thus supporting the notion of oxidative
stress induced colorectal cancer.
Q2: How does ferritin store iron?

Ferritin has the shape of a hollow sphere. Inside the sphere, iron is stored in the
Fe(III) oxidation state. It is incorporated in the mineral ferrihydrite,
[FeO(OH)]8[FeO(H2PO4)], which is attached to the inner wall of the sphere. To
release iron when the body needs it, the iron must be changed from the Fe(III) to
the Fe(II) oxidation state. Then, the iron leaves through channels in the spherical
structure. When the Fe (III) in the crystalline mineral is reduced to Fe(II), the iron
becomes solvated and ferritin releases the solvated iron, ]Fe(H2O)6[2+, through the
3-fold polar channel. Hence, ferritin can control the amount of available iron in the
body, preventing iron disorders like anemia and iron overload.

This figure shows a proposed mechanism of ferroxidase reaction in ferritin.

For simplicity, we show only the side chains of Glu50 and Gln127 at the
ferroxidase center. Two Fe ions are bound at the ferroxidase center (iron-bound),
where an oxygen molecule binds in a side-on mode (oxygen-bound: subunitC),
oxidizes the Fe ions, and subsequently produces a peroxodiferric intermediate
(peroxodiferric: subunitD). The side-on peroxo in non-planar butterfly geometry is
unstable and decays to oxodiferric form (subunits A, B, and E) and generates
hydrogen peroxide. Red arrow indicates side chain flipping of Gln127.
Q3: Draw a schematic diagram of iron absorption and regulation?

Food contains iron enter the gastrointestinal tract of human, in stomach iron
extracted from the food by helping of stomach acid. If the iron of plants origin it
will be in ferric state which need enzymatic conversion by cytochrome B enzyme
to be ferrous state and enter the Mucosal cell through DMT1but if the iron of
animals origin it will be in ferrous state which ready to absorbed by mucosal cell
through Heme carrier protein 1. After entering the mucosal cell iron have two ways
to follow, first way is to storage in mucosal cell as mucosal ferritin or second way
entering the blood through ferroportin 1 as plasma transferring. HFE gene protein
on sensor cell determines which way iron will follow after measuring serum iron
transferrin by stimulating/inhibiting production of liver hepcidin. when Serum iron
transferern is high, sensor cell stimulates hepcidin production by liver which
blocks Ferroportin 1 Channel and make absorbed iron storage as mucosal ferritin
but if serum iron transferrin is low, sensor cell inhibit hepcidin production by liver
and make ferroportin 1 channel open to make absorbed iron enter the blood as
transferrin.