Thioredoxin fromBrugia malayi:Defining a 16-Kilodalton Class of Thioredoxins from Nematodes

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Abstract
Thioredoxins are a family of small redox proteins that undergo NADPH-dependent reduction by thioredoxin reductase. This results in a supply of reducing equivalents that cells use in a wide variety of biological reactions, which include maintaining reduced forms of the enzymes important for protection against damage from high-energy oxygen radicals, the regulation of transcription factor activity, and the inhibition of apoptosis. Here we report on a new member of the thioredoxin family of proteins from the filarial nematodeBrugia malayi,Bm-TRX-1, which defines a new subclass of 16-kDa thioredoxins that occur widely in nematodes, includingCaenorhabditis elegans. In addition to being larger than the thioredoxins found in mammalian and bacterial species, the putative active site sequence ofBm-TRX-1, WCPPC, does not conform to the highly conserved WCGPC reported for thioredoxins from mammals to bacteria. Interestingly, an allelic form ofBm-TRX-1 was identified with an active site sequence WCPQC, which appears to be unique to the thioredoxins from filarial species.Bm-TRX-1 was between 98% and 35% identical to thioredoxins from other nematodes and ≈20% identical to the thioredoxins from mammals andEscherichia coli. Bm-TRX-1 was constitutively transcribed throughout theB. malayilife cycle, andBm-TRX protein was detectable in somatic extracts and excretory-secretory products from adults and microfilariae. RecombinantBm-TRX-1 had thiodisulfide reductase activity, as measured by the reduction of insulin, and protected DNA from the nicking activity of oxygen radicals. Overexpression ofBm-TRX-1 in a human monocyte cell line negatively regulated tumor necrosis factor alpha-induced p38 mitogen-activated protein kinase activity, suggesting a possible role of the 16-kDaBm-TRX-1 in immunomodulation.