Research

Heme-derived bilins

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 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 (Takemoto et al., 2019).  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)

Figure 3.  Heme and bilins in mammals

Figure 3. Heme  and bilins and their  metabolism in red blooded mammals.  Heme (1) is catabolized to biliverdin IX⍺ , 2 and bilirubin, 6.  6 is  glycosylated and metabolized to urobilinogen, 8 , urobilin, 7 and mesobiliverdin IX⍺ (also called glaucobilin), 16.  We study and biomanufacture 2 and 16 which are  bioactive , cytoprotective  and natural anti-oxidants and anti-inflammatories.   Open arrows indicate bilin excretion from an organ (e.g. intestine and kidney). Dashed arrows depict major (long dashes) and minor (short dashes) transport rates of bilins to and from bile of the gall bladder.  Key enzymes  shown are :  HO-1, heme oxygenase-1; BVRA, biliverdin reductase A; UGT, uridine 5′-diphosphate glucuronosyl transferase.  (Based on Takemoto et al.  2019. Heme-derived bilins. Isr. J. Chem.  59:378-386.)eHeme and Bilins in Mammals:

me and Bilins in Mammals

Current bilin research projects

Figure 4 . 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.   Details are described in Chang, C.-W. T.;  Takemoto, J. Y.;  Chang, P.-E.;  AlFindee, M. N.; Lin, Y.-Y., Effects of Mesobiliverdin IXα-Enriched Microalgae Feed on Gut Health and Microbiota of Broilers. Frontiers in Veterinary Science 2021, 7 (1225).

Figure 4 . 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.   Details are described in Chang, C.-W. T.;  Takemoto, J. Y.;  Chang, P.-E.;  AlFindee, M. N.; Lin, Y.-Y., Effects of Mesobiliverdin IXα-Enriched Microalgae Feed on Gut Health and Microbiota of Broilers. Frontiers in Veterinary Science 2021, 7 (1225).