Heme-derived bilins are tetrapyrroles that play important biological roles such as light-sensing, light-harvesting, blood metabolism, and innate defense (Takemoto et al. 2019) . Central to these functions is the evolutionary conserved enzyme heme oxygenase 1 (HO-1) that breaks the closed ring tetrapyrrole heme (structure 1, Figure 1) to release iron, CO and biliverdin IXα (structure 2, Figure 1). Biliverdin IXα is the precursor to several heme-derived metabolites that include bilirubin, urobilins, stercobilins, and mesobiliverdin IXα (Figure 2) in animals and phycobilins in plants and photosynthetic microbes. Bilirubin, biliverdin IXα and mesobiliverdin IXα are strong antioxidants and cytoprotective against inflammatory conditions. Our research goals are to use microbial systems to scalably produce these bilins by exploiting their evolutionary relatedness and that will facilitate their use in medical and agricultural applications. Examples of targeted applications are cytoprotection for stem cell and tissue xenotransplantion therapies and medicinal livestock feed.
biliverdin IX⍺
Figure 1. Four ways that heme oxygenase (HO) breaks heme to make biliverdin. Heme (1) and biliverdin isomers (2-5) after methene bridge cleavage at the ⍺, β, 𝛾 or 𝜹 positions by heme oxygenases . Isomer biliverdin IXα (2) is bioactive, an anti-oxidant, produced by heme oxygnase-1 (HO-1) and the most common of the 4 biliverdin isomers .
Figure 2. Mesobiliverdin IXα , also named "glaucoblin" in the older bilin literature, is a close structural analog and functional mimic of biliverdin IXα (structure 2, Figure 1)
Scalable production of mesobiliverdin IXα
Bilin cytoprotection against oxidative stress of mesenchymal stem cells, lung tissues, pancreatic islets , retinal pigmented epithelial cells, and gut epithelial cells
Mesobiliverdin IXα-enriched medicinal animal feed (examples below)
Amelioration of osteoporosis by mesobiliverdin IXα
Mesobiliverdin IXα as a potential therapeutic against long COVID-19
Examples of recent animal feed studies:
Histological analysis of broiler small intestine duodenum after feeding with basal diet normal feed (1st panel), feed supplemented with amoxicillin (2nd panel), or feed supplemented with microalgae extract enriched with 0.1% mesobiliverdin IXα (3rd panel). Shown are representative histological images of duodenum intestinal segment sections stained with hematoxylin and eosin and viewed at X40 magnification with scale bars indicating 500 μm. Duodenum segments of broilers fed with feed supplemented with mesobiliverdin IXα -enriched microalgae extract have significantly longer villi than those fed with unsupplemented feed or with feed supplemented with amoxicillin suggesting less intestinal inflammation with mesobiliverdin IXα -enriched microalgae extract supplementation.
Mesobiliverdin IXα-enriched microalgae feed additive eliminates reliance on antibiotic tylosin and promotes intestinal health of weaning piglets. From Liao, T.-S.; Chen, C.-Y.; Lin, C.-S.; Chang, C.-W. T.; Takemoto, J. Y.; Lin, Y.-Y. J Animal Physiol Animal Nutri 2023, 107 (6), 1368-1375. DOI: https://doi.org/10.1111/jpn.13867 (acccessed 2023/08/07).
Effects of tylosin, and mesobiliverdin IXα-enriched algal supplementation of feed on proinflammatory cytokines (a) IL-6 and (b) TNF-α in intestinal tissues of weaning piglets. IL-6, interleukin-6; MBV-SP1, basal feed plus 0.1% mesobiliverdin IXa-enriched algal extract; MBV-SP2, basal feed plus 0.5% mesobiliverdin IXa-enriched algal extract; NC, basal diet; PC, basal diet plus 0.05% tylosin (antibiotic). Levels of gut proinflammatory cytokines IL-6 and TNF-α are significantly lower with mesobiliverdin IXα-enriched algal supplementation of feed (at 0.5%) as compared to unsupplemented feed and comparable to tylosin-containing feed. Data were expressed as the mean ± SEM (n = 4). Bars with different letters were significantly different (p <0.05) by Tukey's test. SEM, standard error of the mean; TNF-α, tumour necrosis factor-alpha.