Bone marrow inhibition induced by azathioprine in a patient without mutation in the thiopurine S-methyltransferase pathogenic site:A case report

BACKGROUND Azathioprine(AZA)and its close analog 6-mercaptopurine are thiopurines widely used in the treatment of patients with cancer,organ transplantation,and autoimmune or inflammatory diseases,including systemic lupus erythematosus.Bone marrow inhibition is a common side effect of AZA,and severe bone marrow inhibition is related to decreased thiopurine S-methyltransferase(TPMT)activity.CASE SUMMARY We herein report a patient with proliferative lupus nephritis who was using AZA for maintenance therapy,had no common TPMT pathogenic site mutations,and exhibited severe bone marrow inhibition on the 15th day after oral administration.CONCLUSION This report alerts physicians to the fact that even though the TPMT gene has no common pathogenic site mutation,severe myelosuppression may also occur.

Mechanistic insights into the key marine dimethylsulfoniopropionate synthesis enzyme DsyB/DSYB

Marine algae and bacteria produce approximately eight billion tonnes of the organosulfur molecule dimethylsulfoniopropionate(DMSP)in Earth's surface oceans annually.DMSP is an antistress compound and,once released into the environment,a major nutrient,signaling molecule,and source of climate-active gases.The methionine transamination pathway for DMSP synthesis is used by most known DMSP-producing algae and bacteria.The S-directed S-adenosylmethionine(SAM)-dependent 4-methylthio-2-hydroxybutyrate(MTHB)S-methyltransferase,encoded by the dsyB/DSYB gene,is the key enzyme of this pathway,generating S-adenosylhomocysteine(SAH)and 4-dimethylsulfonio-2-hydroxybutyrate(DMSHB).DsyB/DSYB,present in most haptophyte and dinoflagellate algae with the highest known intracellular DMSP concentrations,is shown to be far more abundant and transcribed in marine environments than any other known S-methyltransferase gene in DMSP synthesis pathways.Furthermore,we demonstrate in vitro activity of the bacterial DsyB enzyme from Nisaea denitrificans and provide its crystal structure in complex with SAM and SAH-MTHB,which together provide the first important mechanistic insights into a DMSP synthesis enzyme.Structural and mutational analyses imply that DsyB adopts a proximity and desolvation mechanism for the methyl transfer reaction.Sequence analysis suggests that this mechanism may be common to all bacterial DsyB enzymes and also,importantly,eukaryotic DSYB enzymes from e.g.,algae that are the major DMSP producers in Earth's surface oceans.