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Doubly Protonated Species Collision Induced Dissociation for Identification of Isocyclosporins

Nonribosomal cyclopeptide cyclosporin A (CsA), produced by fungus Tolypocladium inflatum, is an extremely
important immunosuppressive drug used in organ transplantations and for therapy
of autoimmune diseases. Here we report for the first time production of CsA,
along with related cyclosporins B and C, by Tolypocladium
inflatum strains of marine origin (White Sea). Cyclosporins A–C contain an
unusual amino acid, (4R)-4-((E)-2-butenyl)-4,N-dimethyl-l-threonine
(MeBmt), and are prone to isomerization to non-active isocyclosporine by N→O
acyl shift of valine connected to MeBmt in acidic conditions. CsA and isoCsA
are not distinguishable in MS analysis of [M+H]+ ions due to the rapid
[CsA+H]+→[isoCsA+H]+ conversion. We found that the N→O
acyl shift is completely suppressed in cyclosporine [M+2H]2+ ions,
and their MS/MS fragmentation can be used for rapid and unambiguous analysis of
cyclosporins and isocylosporins. The fragmentation patterns of [CyA+2H]2+
and [isoCyA+2H]2+ ions were analyzed and explained. The developed
approach could be useful for MS analysis of other peptides containing β-hydroxy-α-amino
acids.