Bilin-dependent regulation of chlorophyll biosynthesis by GUN4.

Biosyntheses of chlorophyll and heme in oxygenic phototrophs share a common trunk pathway that diverges with insertion of magnesium or iron into the last common intermediate, protoporphyrin IX. Since both tetrapyrroles are pro-oxidants, it is essential that their metabolism is tightly regulated. Here, we establish that heme-derived linear tetrapyrroles (bilins) function to stimulate the enzymatic activity of magnesium chelatase (MgCh) via their interaction with GENOMES UNCOUPLED 4 (GUN4) in the model green alga Chlamydomonas reinhardtii A key tetrapyrrole-binding component of MgCh found in all oxygenic photosynthetic species, CrGUN4, also stabilizes the bilin-dependent accumulation of protoporphyrin IX-binding CrCHLH1 subunit of MgCh in light-grown C. reinhardtii cells by preventing its photooxidative inactivation. Exogenous application of biliverdin IXα reverses the loss of CrCHLH1 in the bilin-deficient heme oxygenase (hmox1) mutant, but not in the gun4 mutant. We propose that these dual regulatory roles of GUN4:bilin complexes are responsible for the retention of bilin biosynthesis in all photosynthetic eukaryotes, which sustains chlorophyll biosynthesis in an illuminated oxic environment.

Pleiotropic functions of biliverdin reductase: cellular signaling and generation of cytoprotective and cytotoxic bilirubin.

Degradation of heme requires its conversion to biliverdin (BV) by heme oxygenase, followed by reduction of BV to the free-radical quencher bilirubin (BR) by biliverdin reductase (BVR). It is now recognized that human BVR (hBVR) is a dual-specificity kinase (Ser/Thr and Tyr) upstream activator of the insulin/insulin growth factor-1 (IGF-1) and mitogen-activated protein kinase (MAPK) signaling pathways. hBVR is also a basic-leucine-zipper (bZip) DNA/chromatin-binding transcription factor, an activator and anchor protein for translocation of protein kinase C betaII and zeta isozymes within cell compartments, and a kinase kinase for their activation. hBVR is essential for MAPK-extracellular signal-regulated kinase (ERK)1/2 (MEK)-eukaryotic-like protein kinase (Elk) signaling and has been identified as the cytoplasm-nuclear heme transporter of ERK1/2 and hematin, the key components of stress-responsive gene expression. Here, we discuss the recently uncovered functions of hBVR in cell signaling and regulation of gene expression, and the role of BR in cellular signaling, cytoprotection and cytotoxicity.

A beneficial role of bile pigments as an endogenous tissue protector: anti-complement effects of biliverdin and conjugated bilirubin.

Bile pigments possess an anti-complement property and could be involved in tissue protection. In this study, we examined the physiological actions of bile pigments, which had been generally regarded as waste catabolites. Biliverdin inhibited complement cascade reactions in vitro, especially at the C1 step in the classical pathway at low micromolar concentrations. Further, Forssman anaphylaxis in guinea pigs, being closely associated with complement reactions, was inhibited by oral or intravenous administration of biliverdin. Conjugated bilirubin also showed an inhibitory effect on complement-dependent reactions in vitro. From these observations, we propose a hypothesis that the pigments serve as endogenous tissue protectors by multiple lines of mechanisms including antioxidant and anti-complement actions.

Potassium flux and leaf movement in Samanea saman. II. Phytochrome controlled movement.

Phytochrome, a membrane-localized biliprotein whose conformation is shifted reversibly by brief red or far-red light treatments, interacts with the rhythmic oscillator to regulate leaflet movement and potassium flux in pulvinal motor cells of Samanea. Darkened pinnae exposed briefly to red light (high P(fr) level) have less potassium in motor cells in the extensor region, more potassium in motor cells in the flexor region, and smaller angles than those exposed to far-red light (low P(fr) level). Increase in temperature from 24 degrees to 37 degrees increases the differential effect of the light treatments during opening (the energetic phase) but not during closure, implying that phytochrome controls an energetic process. It seems likely that phytochrome interacts with rhythmically controlled potassium pumps in flexor and extensor cells. During nyctinastic closure of white-illuminated pinnae, exposure to far-red light before darkening results in larger angles than does exposure to red. As in rhythmic opening, the angles of all pinnae and the differential effect of the light treatments increases with increasing temperature.

Optical properties and structure of tetrapyrroles. A report of a symposium held at the University of Konstanz, FRG, August 12-17, 1984.

Many basic life processes such as oxygen transport, electron transport, photosynthesis and plant development, are mediated by tetrapyrroles. It has long been recognized that optical and other physicochemical properties of tetrapyrroles are highly important not only for characterization of the various relevant systems but also to provide a key role in the understanding of their structural and functional aspects. The symposium described below was devoted mainly to recent advances in the optical and molecular properties of biologically important systems, involving both cyclic and open-chain tetrapyrroles. The topics presented and discussed ranged from physics and chemistry to plant biology and medicine. This interdisciplinary character of the meeting conforms with previous symposia also held in Konstanz: Protein-Ligand Interactions (1974) and Transport by Proteins (1978) [see FEBS Lett. (1975) 54, 1-4, and FEBS Lett. (1979) 103, 1-4]. In order to stimulate exchange of ideas, new experimental approaches and techniques, emphasis was placed on the discussions following each presentation, reports of which are also included in the book published. Preprints of the papers presented were distributed some time prior to the symposium. The symposium was mainly supported by the Stiftung Volkswagenwerk and the University of Konstanz. The meeting was based on 29 invited lectures which were divided into four sections.

Potential application of biliverdin reductase and its fragments to modulate insulin/IGF-1/MAPK/PI3-K signaling pathways in therapeutic settings.

The range and diversity of functions of biliverdin reductase (BVR) is unmatched by any enzyme characterized to date. BVR is the sole catalyst for the conversion of biliverdin-IXα the activity product of the stress-inducible HO-1 and the constitutive HO-2, to bilirubin-IXα. Bilirubin is both cytoprotective and cytotoxic, quenches reactive oxygen species (ROS) and inhibits inflammatory and mitogen-induced ROS-mediated responses, and its elevated levels in the newborn adversely effects neuronal cells. Thus, BVR occupies a center stage in cellular defense mechanisms. As a dual specificity (serine/threonine/tyrosine) kinase the human (h) BVR influences transduction of extracellular stimuli to kinases downstream of the insulin/IGF-1(insulin-like growth factor-1)/MAPK/PI3-K signaling pathways. As a bZip-type transcription factor it binds to AP-1 (activator protein-1) and CRE (cAMP response element) sites and stimulates stress-inducible gene expression; as a scaffold protein, it is a platform for interaction of kinases; while acting as an intracellular shuttle, it transports regulatory factors to their target sites. hBVR promoter has consensus sequences with several regulatory elements. The gene is subject to negative and positive regulation, respectively, by TNF-α (tumor necrosis factor-α) and oxidative stress/hypoxia. Small human BVR-based peptides effectively duplicate polypeptide's activating influence on kinases, or mimic inhibitors of cell signaling. This, points to a realistic prospect of their use in clinical settings. The present review will briefly update cytoprotective activity and cytotoxicity of bile pigments and will focus on findings that link hBVR to cell signaling.

The action spectrum and phototransformations of pterobilin (biliverdin IX gamma).

Pterobilin 1 (biliverdin IX gamma), a butterfly bile pigment, is photocyclized into phorcabilin 2 and sarpedobilin 3 by irradiation in visible light. Selective irradiations have now been performed at the absorption maxima of pterobilin 1. The 650-nm radiations are responsible for the observed photocyclizations while the 375-nm radiations lead to decomposition products. These results are discussed in connection with a hypothesis concerning the biological role of pterobilin in butterfly larvae.

[Physiology and pathophysiology of bile secretion]. / Physiologie und Pathophysiologie der Gallensekretion.

After introductory anatomical considerations a survey is given of the composition of bile and the physiology of bile secretion. According to the modern conception the bile acids give the osmotic power for the excretion of water and electrolytes. Apart from this, a bile fraction, which is also secreted by the liver cells into the canaliculi, is present, and in the biliary ducts a further volume fraction independent of bile acid is added, the secretion of which is determined by gastrointestinal hormones. Processes of reabsorption play a role particularly in the gallbladder. By formation of micelles the bile salts render the excretion of cholesterol possible. A normal bile secretion is necessary for the normal emulgation, digestion and absorption of the fats.

Carbon monoxide and bile pigments: surprising mediators of vascular function.

Heme oxygenase (HO) catalyzes the degradation of heme to CO, iron, and biliverdin. Biliverdin is subsequently metabolized to bilirubin by the enzyme biliverdin reductase. Although long considered irrelevant byproducts of heme catabolism, recent studies indicate that CO and the bile pigments biliverdin and bilirubin may play an important physiological role in the circulation. The release of CO by vascular cells may modulate blood flow and blood fluidity by inhibiting vasomotor tone, smooth muscle cell proliferation, and platelet aggregation. CO may also maintain the integrity of the vessel wall by directly blocking vascular cell apoptosis and by inhibiting the release of pro-apoptotic inflammatory cytokines from the vessel wall. These effects of CO are mediated via multiple pathways, including activation of soluble guanylate cyclase, potassium channels, p38 mitogen-activated protein kinase, or inhibition of cytochrome P450. In addition, the release of bile pigments may serve to sustain vascular homeostasis by protecting vascular cells from oxidative stress and by inhibiting the adhesion and infiltration of leukocytes into the vessel wall. Induction of HO-1 gene expression and the subsequent release of CO and bile pigments are observed in numerous vascular disorders and may provide an important adaptive mechanism to preserve homeostasis at sites of vascular injury. Thus, the HO-catalyzed formation of CO and bile pigments by vascular cells may function as a critical endogenous vasoprotective system. Moreover, pharmacological or genetic approaches targeting HO-1 to the vessel wall may represent a novel therapeutic approach in treating vascular disease.