Cytochrome P450 2A13 is able to oxidise aflatoxin M1 (AFM1) to the reactive aflatoxin M1 epoxide (AFM1E) (He et al. 2006). AFM1E is less carcinogenic or mutagenic than aflatoxin B1-exo-8,9-epoxide (AFBO), but is equally toxic. AFM1E would usually be detoxified by conjugation with glutathione, eventually excreted in urine as a mercapturic acid (not shown here).
Cytosolic arylformamidase (AFMID) catalyzes the hydrolysis of formylkynurenine to yield formate and L-kynurenine. Human AFMID has been identified only as an open reading frame; its activity is inferred from that of its well-characterized mouse homologue (Pabarcus and Casida 2002).
Aflatoxin B1 (AFB1) undergoes extensive oxidation, which is catalysed by cytochrome P450s. In addition to formation of the 8,9-oxide, oxidation by CYP1A2 yields a stable metabolite, aflatoxin M1 (AFM1), that is excreted in milk and urine (Ueng et al. 1995). AFM1 is less carcinogenic or mutagenic than AFB1, but is equally toxic.
Gasdermin D (GSDMD) is a member of the gasdermin (GSDM) protein family, which is processed by inflammatory caspases and cleaved into an N‐terminal (GSDMD(1-275)) and a C‐terminal (GSDMD (276-484)) fragments (Shi J et al, 2015). Once GSDMD is cleaved, the N-terminal fragment of GSDMD (1-275) targets and permeabilizes cellular membranes by assembling transmembrane pores (Ding J et al, 2016; Liu X et al, 2016; Sborgi L et al, 2016). High‐resolution (≤ 2 nm) atomic force microscopy (AFM) showed that GSDMD N-terminus inserts into various lipid membranes (Mulvihill E et al. 2018). Once inserted, the N-terminal fragment of GSDMD assembles arc‐, slit‐, and ring‐shaped oligomers, which eventually incorporate additional oligomers and transform into larger thermodynamically stable ring‐shaped oligomers (Mulvihill E et al. 2018).
Gasdermin D (GSDMD) is cleaved by inflammatory caspases into an N‐terminal (GSDMD(1-275)) and a C‐terminal (GSDMD (276-484)) fragment (Shi et al, 2015). The liposome-based assays indicated that the N-terminal doman of GSDMD (1-275) binds membrane lipids assembling large pores (Ding J et al. 2016; Liu X et al. 2016). High‐resolution (≤ 2 nm) atomic force microscopy (AFM) showed that the GSDMD N-terminus inserts into various lipid membranes (Mulvihill E et al. 2018). Once inserted, the N-terminal fragment of GSDMD assembles arc‐, slit‐, and ring‐shaped oligomers, which eventually can incorporate additional oligomers and transform into larger thermodynamically stable ring‐shaped oligomers (Mulvihill E et al. 2018). Ca2+ influx through GSDMD pores was shown to recruit the endosomal sorting complexes required for transport (ESCRT) machinery to damaged areas of the plasma membrane, leading to membrane repair. ESCRT-III–dependent membrane repair is thought to negatively regulate cell death and interleukin (IL)-1β, IL18 secretion following inflammasome activation (Rühl S et al. 2018).
Human gasdermin D (GSDMD) is a member of the gasdermin (GSDM) protein family, which is processed by inflammatory caspases and cleaved into N‑terminal (GSDMD(1‑275)) and C‑terminal (GSDMD(276‑484)) fragments (Shi et al. 2015). The N‑terminal fragment of GSDMD (1‑275) by itself caused pyroptosis when expressed ectopically in human embryonic kidney HEK293 cells, whereas the overexpression of the GSDMD C‑terminus was found to block pyroptosis (Shi et al, 2015). The N‑terminal fragment, GSDMD (1‑275), targets and permeabilizes cellular membranes by assembling transmembrane pores (Ding et al, 2016; Liu X et al, 2016; Sborgi et al, 2016; Mulvihill et al. 2018). High‐resolution (≤ 2 nm) atomic force microscopy (AFM) showed that the N‑terminal fragment of GSDMD inserts into various lipid membranes (Mulvihill E et al. 2018). The lipid composition of the membrane was found to directly influence the ability of GSDMD to permeabilize liposomes (Ding et al, 2016; Liu et al, 2016; Mulvihill et al. 2018). Whereas phosphoinositides (PIPs) facilitated binding of GSDMD (1‑275), cholesterol reduced insertion of GSDMD (1‑275) and pore formation (Ding et al, 2016; Sborgi et al, 2016; Mulvihill et al. 2018). Once inserted, GSDMD (1‑275) assembles arc‐, slit‐, and ring‐shaped oligomers (Ding et al, 2016; Liu et al, 2016; Sborgi et al, 2016; Mulvihill et al. 2018).