Sandbox Reserved 431

This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439.

Vitamin D activation by cytochrome P450, Rickets (3c6g)

by Isabel Hand, Elizabeth Humble, Kati Johnson, Samantha Kriksceonaitis, and Matthew Tiller

Student Projects for UMass Chemistry 423 Spring 2016 <StructureSection load='3c6g' size='350' side='right' caption='caption for Molecular Playground (PDB entry 3c6g)' scene=>

Introduction

Rickets is a disease caused by a vitamin D deficiency. Vitamin D can be obtained from ultra violet radiation and from various food sources. Cytochrome P450 enzymes are involved in the first step to regulate and process vitamin D in the human body. Human P450

Overall Structure

Cytochrome P450 exists as an asymmetric dimer. Each dimeric unit contains 12 α-helices (labeled A-L) along with β-sheets, which are mostly located on one side of the molecule. Helices F and G from each of the two units form the dimeric interface of cytochrome P450, and are also involved in the formation of the active site. This dimeric interface of the protein is stabilized by hydrogen bonding interactions between the G helix of one the units with the F helix of the second unit, and vice versa. Two molecules of 2-hydroxypropyl-β-cyclodextrin, which is used to dissolve vitamin D3, are also found near the dimer interface.

Binding Interactions

The binding of Vitamin D3 occurs in a channel between the G and I helices and B' helix and B-C loop. In the Space filling representation you can see the residues that interact to bind Vitamin D3 and the channel between. Most of these residues are hydrophobic and thus have non polar interactions. Binding of the substrate causes the access channel to close. The B' helix has a flexible C terminus and can adopt a helix or loop conformation, which has van der waal interactions with the F-G loop. The B' helix unwinds outward to allow entrance of the substrate into the active site channel. CYP2R1 has an extended binding site where the access channel is part of the active site. -catalyzes initial step for converting vitamin D into 25-hydroxyvitamin D -mutation causes rickets-25-hydroxylase deficiency

Additional Features

Cytochrome P45 has a central iron-bound heme, which, combined with its structural conformation, allows for hydroxylation with the attached substrate. Cytochrome P450 has specific vitamin D 25-hydroxylase activity, which does not function properly when a person has rickets. Rickets is caused when a person lacks sufficient vitamin D in their system, which is often caused by a vitamin D-25 hydroxylation defect. Leu99Pro is an evolutionarily conserved mutation in the beta helix which contributes to the hydroxylation defect. Leu99 does not inhibit substrate binding; however, Leu99Pro disturbs hydrogen binding around the heme and interferes with the helix steric properties, causing protein instability. When Leu99 does not have the proline mutation, its carboxyl group forms hydrogen bonds with Arg445 which are both located around the central heme.

Heme Group

Quiz Question 1

(merely an example of what this section might look like)

rom this orientation can you identify the green, red, and blue parts of the molecule?

See Also

• Cytochrome P450
• Drug Metabolism by CYP450 Enzymes
• 3w0y
• 3w0c

Credits

Introduction - Sami Kriksceonaitis

Overall Structure - Kati Johnson

Drug Binding Site - Isabel Hand

Additional Features - Elizabeth Humble

Quiz Question 1 - Matthew Tiller1