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Title: Insertion of cobalt into tetrapyrroles
Vitamin B12 is one of the most complex cofactors known, and this chapter will discuss current understanding with regards to the cobalt insertion step of its syntheses. Two total syntheses of vitamin B12 were reported in the 1970s, which remain two of the most exceptional achievements of natural product synthesis. In subsequent years, two distinct biosynthetic pathways were identified in aerobic and anaerobic organisms. For these biosynthetic pathways, selectivity for Co(II) over other divalent metal ions with similar ionic radii and coordination chemistry remains an open question with three competing hypotheses proposed: metal affinity, tetrapyrrole distortion, and product inhibition. A 20 step biosynthetic route to convert 5-aminolevulinic acid (ALA) to vitamin B12 was elucidated in aerobic organisms in the 1990s, where cobalt is inserted relatively late in the pathway by the CobNST multi-protein complex. This chapter includes a mechanistic proposal for this reaction, but the majority of the proposal is based upon analogy to the ChlDHI magnesium chelatase complex as critical data for the cobalt chelatase is lacking. Later, in the 2010s, a distinct 21 step pathway from ALA to vitamin B12 was reported in anaerobic organisms, where cobalt is inserted early in the pathway by the enzyme CbiK. A recent study strongly suggests that the cobalt affinity of CbiK is the origin of cobalt selectivity for CbiK, but several important mechanistic questions remain unanswered. In general, it is expected that significant insight into the cobalt insertion mechanisms of CobNST and CbiK could be derived from additional structural, spectroscopic, and computational data.  more » « less
Award ID(s):
2003627
PAR ID:
10346441
Author(s) / Creator(s):
; ;
Editor(s):
Litwack, G.
Date Published:
Journal Name:
Vitamins and hormones
Volume:
119
ISSN:
0083-6729
Page Range / eLocation ID:
1-22
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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