Abstract:
Molybdenum cofactor deficiency (MoCD) is a rare, autosomal recessive, metabolic disorder,
categorized by the deficit of molybdenum cofactor (MoCo) in the body. Molybdenum Cofactor
Deficiency Type B occurs when the cyclic pyranopterin (cPMP), the first intermediate in the
biosynthesis of MoCo, is unable to convert into the Metallopterin (MPT) which is the second
intermediate of MoCo biosynthesis. To understand the reason, first step was to understand the
formation of MPT from cPMP with the help of Molybdenum Synthase (MOCS2) and then to
identify the reasons behind MoCD Type-B. According to the reaction mechanism studies in this
research MPT formation from cPMP is a two-step mechanism, both with the help of Gly-76 amino
acid residue: (1) Formation of mono-thiolated cPMP, and (2) Formation of MPT. According to the
computational results the energy barrier required for the formation of monothiolated cPMP is
142.1 kcal/mol whereas formation of MPT from mono-thiolated cPMP require the 124.0 kcal/mol
energy, therefore, the mono-thiolated cPMP formation from cPMP is the rate limiting step. To find
the reason for the MoCD Type B, mutational analysis data was compared with the results obtained
from the binding pocket analysis for cPMP and it has been observed that the Gly-76 was mutated
to Arg-76 which is a much bulkier group then Glycine. Hence, the thiolation of Arg and the transfer
of -SH group to cPMP is not possible which leads to the MoCD Type B.
