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Vitamin D – millions of years more ancient than Calcium – Jan 2016

Vitamin D: a dynamic molecule. How relevant might the dynamism for a vitamin be?

Nephrology Dialysis Transplantation Volume 31, Issue 1Pp. 23-30.
Sandro Mazzaferro1, sandro.mazzaferro at uniroma1.it and Marzia Pasquali1
1Department of Cardiovascular Respiratory Nephrologic Anesthetic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
2Nephrology and Dialysis Unit, Policlinico Umberto I Hospital, Rome, Italy
Received June 22, 2015. Accepted August 22, 2015.

 Download the PDF from VitaminDWiki
Cholecalciferol, the precursor of Vitamin D3, is a very old, highly conserved, molecule. Its presence is evident in non-mineralized 750 million-year-old living species, such as plankton. The more active metabolites, a receptor and a D binding protein, appear later, along with the increasing complexity of animal species living in the sea. In the sea, however, the biological function of vitamin D is unlikely to be linked with mineral metabolism, and we can hypothesize a relationship with an immune response. It is in terrestrial animals exhibiting cellular bone that the complexity of vitamin D increases. At this stage of evolution, we see the appearance of bone cells that are capable of producing hormones that regulate and are regulated by vitamin D. This interaction starts a sophisticated metabolic system that modulates both mineral and energy metabolism for the requirements of the musculoskeletal system. Among the so-called pleiotropic effects of vitamin D, those resulting from the inhibitory effect on the renin-angiotensin system are of particular interest for nephrologists. Intriguingly, however, more than for anti-hypertensive effects, this interaction could be relevant for anti-inflammatory actions, possibly representative of a residual ancestral role of vitamin D. In addition, this evolutionary dynamism of the vitamin D system should not be separated from the chemical dynamism that characterizes the ligand molecule and its specific receptor. Both are capable of significant tridimensional modifications that contribute to an increase in the variability and the partial predictability of their final biological effect. A dynamic overview of this system that takes into account its evolutionary and adaptive aspects may be helpful to understand its biological complexity and to envisage why using vitamin D metabolites for therapeutic purposes is still a matter of debate.


Vitamin D should be regarded as a very conserved molecule that probably started as a component of the plasma membrane of simple organisms, with protective or defensive roles. Its function has changed to become a necessary regulatory element of the metabolic and energetic requirements of life on Earth. The dynamism of the molecule and its receptor certainly represents an element of the plasticity that allowed the acquisition of such highly specialized properties within the musculoskeletal system. It is impressive that during evolution the appearance of cellular bone increases the complexity of the system, with the production of bone proteins that counter-regulate the effects of vitamin D on bone and muscles. Significantly, the VDR, possibly because of its ancestral biological roles, is present in numerous tissues not necessarily involved with the musculoskeletal system. Among the claimed pleiotropic properties, the systemic but generic anti-inflammatory effects could be related to the RAS-inhibitory properties. Given this complex biology, it seems rather simplistic to try to deduce its function through the assay of one or two blood circulating metabolites. A dynamic view of the interaction with its receptor is certainly helpful to try to understand why we cannot exactly predict the biological effects of the natural compounds. In fact, the recommended doses of this ‘vitamin’ either for healthy people or for patients are still a matter of debate. A dynamic view also helps to understand why synthetic analogues can have very specific biologic effects and can be considered for very different clinical purposes (from cancer to infection) through activation of the same receptor. Vitamin D and its receptor should be regarded as a rather sophisticated molecular machine that we are still discovering. Much more remains to be discovered, but a general overview that takes into account the evolutionary aspects of this system seems useful to try to understand the multifaceted biology of this ‘vital amine’.

Notes on evolutionary history of Vitamin D after reading the PDF
550 million years ago Vitamin D involved in mineralization of snails etc,
450 million years ago Vitamin D Receptor and Vitamin D Binding Protein
Has a nice chart of Vitamin D-related features vs 100's millions of years
Vast majority of the article deals with the structure of Vitamin D and that of the VDR

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