Complex Of Retinol Research Articles

Methodology for Studying Interactions of Vitamin A Membrane Receptors and Opsin Protein with their Ligands in Generating the Retinylidene Protein.

Distribution of dietary vitamin A/all-trans retinol (ROL) throughout the body is critical for maintaining retinoid function in peripheral tissues and generating the retinylidene protein for visual function. RBP4-ROL is the complex of ROL with retinol-binding protein 4 (RBP4), which is present in the blood. Two membrane receptors, Retinol Binding Protein 4 Receptor 2 (RBPR2) in the liver and STimulated by Retinoic Acid 6 Retinol (STRA6) in the eye, bind circulatory RBP4 and this mechanism is critical for internalizing ROL into cells. Establishing methods to investigate receptor-ligand kinetics is essential in understanding the physiological function of vitamin A receptors for retinoid homeostasis. Using Surface Plasmon Resonance (SPR) assays, we can analyze the binding affinities and kinetic parameters of vitamin A membrane receptors with its physiological ligand RBP4. These methodologies can reveal new structural and biochemical information of RBP4-binding motifs in RBPR2 and STRA6, which are critical for understanding pathological states of vitamin A deficiency. In the eye, internalized ROL is metabolized to 11-cis retinal, the visual chromophore that binds to opsin in photoreceptors to form the retinylidene protein, rhodopsin. The absorbance of light causes the cis-to-trans isomerization of 11-cis retinal, inducing conformational changes in rhodopsin and the subsequent activation of the phototransduction cascade. Decreased concentrations of serum and ocular ROL can impact retinylidene protein formation, which in turn can cause rhodopsin mislocalization, apoprotein opsin accumulation, night blindness, and photoreceptor outer segment degeneration, leading to Retinitis Pigmentosa or Leber Congenital Amaurosis. Therefore, spectrophotometric methodologies to quantify the G protein-coupled receptor opsin-11-cis retinal complex in the retina are critical for understanding mechanisms of retinal cell degeneration in the above-mentioned pathological states. With these comprehensive methodologies, investigators will be able to better assess dietary vitamin A supply in maintaining systemic and ocular retinoid homeostasis, which is critical for generating and maintaining retinylidene protein concentrations in photoreceptors, which is critical for sustaining visual function in humans.

33252 Novel antiaging retinol complex improves facial photodamage in a Hispanic and Caucasian population

Retinol continues to be a key ingredient to improve facial photodamage. However, retinol stability in convenient and affordable consumer formats - such as day and night cream jars - has been a formulation challenge which can lead to a loss in retinol potency and product discoloration. An antiaging night cream was developed with a novel retinol complex, including a proprietary stabilizing oil system which maximizes retinol potency, pro-ceramides and niacinamide. The objective of this research was to demonstrate efficacy of the novel retinol complex in a mixed Hispanic and Caucasian population.

17952 Novel association of ROL- and ROL complex–mediated elastin and collagen expression with epigenetic changes through miRNA regulators

Retinol (ROL), the criterion standard in reducing the appearance of aging, helps to clinically delay and reduce the signs of skin aging. ROL helps stimulate collagen and elastin production among many skin benefits through a retinoic-acid-mediated transcriptional activation. In addition to a classic ligand-dependent transcriptional activation, recent studies suggest that epigenetic regulation through microRNAs (miRNAs), specific inhibitors of targeted gene translation, may also play a role in the regulation of skin aging. However, no studies demonstrated ROL’s rejuvenating skin benefits could be also associated with epigenetic regulation of miRNAs in human skin. Studies were conducted to discover whether ROL’s support in the stimulation of anti-aging biomarkers collagen and elastin could be associated with epigenetic changes in miRNA expression in human skin cells. Human adult fibroblasts were treated with either ROL or ROL complex (a proprietary discovered combination enhancing ROL activity) for up to 72 hours. mRNA, miRNA, and protein expressions were evaluated. ROL and ROL complex helped induce ELN gene expression and type I collagen protein production. Concomitantly, ROL and ROL complex also caused epigenetic changes by reducing the expression of multiple miRNAs known to inhibit collagen and elastin genes expression. Thus, ROL may also exert its rejuvenating skin benefits through epigenetic regulation of both collagen and elastin that supports increases of extracellular matrix proteins. In conclusion, ROL and ROL complex may exert anti-aging skin benefits through a pleiotropic mode of action, uncovering epigenetics as an additional mechanism to explain and enhance its benefits.

Discovery of Bispecific Antagonists of Retinol Binding Protein 4 That Stabilize Transthyretin Tetramers: Scaffolding Hopping, Optimization, and Preclinical Pharmacological Evaluation as a Potential Therapy for Two Common Age-Related Comorbidities.

Accumulation of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex. We previously identified selective RBP4 antagonists that dissociate circulating RBP4-TTR-retinol complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. However, the release of TTR by selective RBP4 antagonists may be associated with TTR tetramer destabilization and, potentially, TTR amyloid formation. We describe herein the identification of bispecific RBP4 antagonist-TTR tetramer kinetic stabilizers. Standout analogue (±)-44 possesses suitable potency for both targets, significantly lowers mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based assay. This new class of bispecific compounds may be especially important as a therapy for dry AMD patients who have another common age-related comorbidity, senile systemic amyloidosis, a nongenetic disease associated with wild-type TTR misfolding.

A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a model of Stargardt disease without inhibiting the visual cycle.

A primary pathological defect in the heritable eye disorder Stargardt disease is excessive accumulation of cytotoxic lipofuscin bisretinoids in the retina. Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) matches the age-dependent increase in the incidence of the atrophic (dry) form of age-related macular degeneration (AMD) and therefore may be one of several pathogenic factors contributing to AMD progression. Lipofuscin bisretinoid synthesis in the retina depends on the influx of serum retinol from the circulation into the RPE. Formation of the tertiary retinol-binding protein 4 (RBP4)-transthyretin-retinol complex in the serum is required for this influx. Herein, we report the pharmacological effects of the non-retinoid RBP4 antagonist, BPN-14136. BPN-14136 dosing in the Abca4-/- mouse model of increased lipofuscinogenesis significantly reduced serum RBP4 levels and inhibited bisretinoid synthesis, and this inhibition correlated with a partial reduction in visual cycle retinoids such as retinaldehydes serving as bisretinoid precursors. BPN-14136 administration at doses inducing maximal serum RBP4 reduction did not produce changes in the rate of the visual cycle, consistent with minimal changes in dark adaptation. Abca4-/- mice exhibited dysregulation of the complement system in the retina, and BPN-14136 administration normalized the retinal levels of proinflammatory complement cascade components such as complement factors D and H, C-reactive protein, and C3. We conclude that BPN-14136 has several beneficial characteristics, combining inhibition of bisretinoid synthesis and reduction in retinaldehydes with normalization of the retinal complement system. BPN-14136, or a similar compound, may be a promising drug candidate to manage Stargardt disease and dry AMD.

Severe ocular phenotypes in Rbp4-deficient mice in the C57BL/6 genetic background

Retinol-binding protein 4 (RBP4) is a specific carrier for retinol in the blood. In hepatocytes, newly synthesized RBP4 associates with retinol and transthyretin and is secreted into the blood. The ternary transthyretin–RBP4–retinol complex transports retinol in the circulation and delivers it to target tissues. Rbp4-deficient mice in a mixed genetic background (129xC57BL/6J) have decreased sensitivity to light in the b-wave amplitude on electroretinogram. Sensitivity progressively improves and approaches that of wild-type mice at 24 weeks of age. In the present study, we produced Rbp4-deficient mice in the C57BL/6 genetic background. These mice displayed more severe phenotypes. They had decreased a- and b-wave amplitudes on electroretinograms. In accordance with these abnormalities, we found structural changes in these mice, such as loss of the peripheral choroid and photoreceptor layer in the peripheral retinas. In the central retinas, the distance between the inner limiting membrane and the outer plexiform layer was much shorter with fewer ganglion cells and fewer synapses in the inner plexiform layer. Furthermore, ocular developmental defects of retinal depigmentation, optic disc abnormality, and persistent hyaloid artery were also observed. All these abnormalities had not recovered even at 40 weeks of age. Our Rbp4-deficient mice accumulated retinol in the liver but it was undetectable in the serum, indicating an inverse relation between serum and liver retinol levels. Our results suggest that RBP4 is critical for the mobilization of retinol from hepatic storage pools, and that such mobilization is necessary for ocular development and visual function.

Influence of the complex of retinol-vitamin C on skin surface lipids.

Retinol is used to reduce symptoms of skin aging. It affects surface lipids and increases skin regeneration ability. The aim of our study was to investigate the effect of retinol peel on the face and neck skin lipids in women, aged 50-69. The level of secreted sebum was measured using Sebumeter SM15 (Courage & Khazaka, Germany) on the forehead, cheeks, nose, chin, and neck. The measurements were carried out before each of the 3 retinol peel treatments applied at 3-week interval and 3 weeks after the last treatment. A statistically significant increase of lipid film in both U-zone and T-zone and on the neck was observed in the study group. Retinol peel treatments can help to increase the amount of skin surface lipids in women during menopause.

A comparison study of the interaction between β-lactoglobulin and retinol at two different conditions: spectroscopic and molecular modeling approaches

The interaction between bovin β-Lactoglobulin (β-LG) and retinol at two different pH values was investigated by multispectroscopic, zeta potential, molecular modeling, and conductometry measurements. The steady state and polarization fluorescence spectroscopy revealed that complex formation at two different pH values could occur through a remarkable static quenching. According to fluorescence quenching, one set of binding site at pH 2 and two sets of binding sites at pH 7 were introduced for binding of retinol to β-LG that show the enhancement of saturation score of β-LG to retinol in dimmer condition. The polarization fluorescence analysis represented that there is more affinity between β-LG and retinol at pH 7 rather than at pH 2. The effect of retinol on β-LG was studied by UV-visible, circular dichroism (CD), and synchronous fluorescence, which indicated that retinol induced more structural changes on β-LG at pH 7. β-LG–retinol complex formation at two different pH values was recorded via applying resonance light scattering (RLS) and zeta potential. Conductometry and RLS showed two different behaviors of interaction between β-LG and retinol at two different pH values; therefore, dimmer formation played important roles in different behaviors of interaction between β-LG and retinol. The zeta potential was the implied combination of electrostatic and hydrophobic forces which are involved in β-LG–retinol complex at two different pH values, and the hydrophobic interactions play a dominant role in complex formation. Molecular modeling was approved by all experimental results. The acquired results suggested that monomer and dimmer states of β-LG can be induced by retinol with different behaviors.

Transthyretin Induces Insulin-like Growth Factor I Nuclear Translocation Regulating Its Levels in the Hippocampus.

Transthyretin (TTR) is the carrier protein of thyroxine (T4) and binds to retinol-binding protein (RBP)-retinol complex. It is mainly synthesized by both liver and choroid plexuses of the brain. Besides these properties, it has a neuroprotective role in several contexts such as Alzheimer’s disease (AD) and cerebral ischemia. Activation of insulin-like growth factor receptor I (IGF-IR) pathways and increased levels of TTR are associated with absence of neurodegeneration in an AD mouse model. In the present study, we verified that young/adult TTR null mice had decreased levels of IGF-IR in the hippocampus, but not in choroid plexus when compared with wild-type age-matched controls. Moreover, we could also demonstrate that conditional silencing of peripheral TTR did not have any influence in hippocampal IGF-IR levels, indicating that TTR effect on IGF-IR levels is due to TTR mainly synthesized in the choroid plexus. In vitro cellular studies, using NIH3T3 cell line and primary cultured hippocampal neurons, we showed that TTR upregulates IGF-IR at the transcription and translation levels and that is dependent on receptor internalization. Using a GFP-IGF-IR fusion protein, we also found that TTR triggers IGF-IR nuclear translocation in cultured neurons. We could also see an enrichment of IGF-IR in the nuclear fraction, after TTR stimulation in NIH3T3 cells, indicating that IGF-IR regulation, triggered by TTR is induced by nuclear translocation. In summary, the results provide evidence of a new role of TTR as a transcription inducer of IGF-IR in central nervous system (CNS), unveiling a new role in neuroprotection.

Noninvasive assessment of collagen deposition and inflammation in facial skin using in vivo reflectance confocal microscopy following treatment with a novel retinol complex and tretinoin

Noninvasive assessment of collagen deposition and inflammation in facial skin using in vivo reflectance confocal microscopy following treatment with a novel retinol complex and tretinoin

Retinol binding to β-lactoglobulin or phosphocasein micelles under high pressure: Effects of isostatic high-pressure on structural and functional integrity

Embedding of bioactive molecules in food matrices is of interest for food industry to develop new foods or ingredients. The present study aims at deepening understanding of ligand binding to dairy proteins regarded as nano-vehicles, using pressure-assisted technological tools. We compared effects of isostatic high-pressure up to 350–400MPa on the stability and the retinol-binding capacity of β-lactoglobulin (β-LG) or phosphocasein (PC) at pH6.5–6.6. Retinol binding to β-LG changed the intrinsic protein and retinol fluorescence, characterised by fluorescence resonance-energy-transfer (FRET). After correction for inner filter effects, the FRET level estimated for the β-LG–retinol complex at pH6.5 and Patm was compatible with a retinol position at the β-LG surface cleft. Pressurisation of the β-LG–retinol complex induced an irreversible loss of the retinol-ligand above 150MPa. Pressurisation of PC dispersion up to 200MPa induced a marked decrease in the PC intrinsic fluorescence intensity with a concomitant red-shift of the spectral mass centre (CSM) explained by Trp residues exposure to aqueous solvent. The pressure-induced CSM half-transition (P1/2) was 116MPa for PC instead of 183MPa for β-LG. Retinol binding to PC also resulted in important FRET, but PC assemblies partly retained retinol after pressure-release from 400MPa. Interestingly, the pressure-induced dissociation rate of PC assemblies in the 15–35°C temperature range was significantly accelerated at lower temperature, reflecting non-Arrhenius behaviour. PC particle sizes evaluated by dynamic light-scattering, confirmed that the pressure-induced dissociation was practically achieved at 200MPa. Thus PC dissociation paralleled the structural changes determined by fluorescence spectroscopy.

Nearly 200 X-Ray Crystal Structures of Transthyretin: What Do They Tell Us About This Protein and the Design of Drugs for TTR Amyloidoses?

Transthyretin (TTR), a β-strand rich tetrameric protein present in human serum and cerebrospinal fluid is involved in the transport of thyroxine and retinol binding protein:retinol complex (holo-RBP). TTR forms two T4 binding sites at the center of the dimer-dimer interface and contains holo-RBP binding sites on both faces of the tetramer. Dissociation of TTR tetramers followed by misfolding and misassembly results in amyloid fibril formation, the causative agent of four neurodegenerative diseases. Misfolding of wild type TTR in humans over 60 years of age is linked to a sporadic amyloid disease called senile systemic amyloidosis. Single point mutations enhance the amyloidogenicity of TTR, causing familial amyloid cardiomyopathy, familial amyloid polyneuropathy, and central nervous system selective amyloidosis. To date, nearly 200 X-ray crystal structures of TTR and their complexes have been solved. They have provided potential insights into its structure-function relationships with molecular partners, and its interactions with small molecule ligands that inhibit tetramer destabilization and amyloid formation. This review will focus on the key findings of the structural studies of TTR that provided atomic level description of its architecture, the mechanistic role of structural components involved in its function and misfolding, and the progress and limitations towards the design of selective inhibitors for TTR amyloidoses.

Expression of the megalin C-terminal fragment by macrophages during liver fibrogenesis in mice

The low-density-lipoprotein receptor megalin (LRP2, gp330) is strongly expressed in the kidney, where it is responsible for the resorption of metabolites from primary urine. One of the main ligands is the complex of retinol and retinol binding protein. Megalin has been hypothesized to be part of the retinol storage system in liver. Considering the role of hepatic stellate cells in retinol storage and fibrogenesis we investigated mouse strains that developed different degrees of fibrosis after challenge with CCl 4. Immunoblotting revealed the invariable expression of the megalin C-terminal fragment independent of liver damage in all strains. However, only a specific cell population in centrilobular areas of fibrotic livers from DBA/2J mice, which were most susceptible for CCl 4-induced fibrogenesis in our study, was stained using megalin-specific antibodies. Double immunostaining indicated that a subset of hepatic macrophages might represent the megalin-expressing cells in fibrotic liver. Fluorescence activated cell sorting based isolation of hepatic macrophages and megalin specific expression analysis demonstrated the transcription of the whole megalin gene in liver macrophages. We argue that megalin might exhibit a proinflammatory effect by the uptake of retinoids in recruited monocytes, which thereby differentiate to liver macrophages and potentiate fibrogenesis by the release of proinflammatory mediators. Otherwise, megalin might be activated in macrophages during advanced fibrogenesis and act as a negative regulator of proinflammatory genes.

Structure and function of hepatic stellate cells.

Hepatic stellate cells (vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, Ito cells) exist in the space between parenchymal cells and sinusoidal endothelial cells of the hepatic lobule and store 80% of retinoids in the whole body as retinyl palmitate in lipid droplets in the cytoplasm. In physiological conditions, these cells play pivotal roles in the regulation of retinoid homeostasis; they express specific receptors for retinol-binding protein (RBP), a binding protein specific for retinol, on their cell surface, and take up the complex of retinol and RBP by receptor-mediated endocytosis. Hepatic stellate cells in arctic animals such as polar bears and arctic foxes store 20-100 times the levels of retinoids found in humans or rats. In pathological conditions such as liver fibrosis, hepatic stellate cells lose retinoids, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, and adhesive glycoproteins. Morphology of these cells also changes from the star-shaped stellate cells to that of fibroblasts or myofibroblasts. The three-dimensional structure of ECM components was found to regulate reversibly the morphology, proliferation, and functions of the hepatic stellate cells. Molecular mechanisms in the reversible regulation of the stellate cells by ECM imply cell-surface integrin binding to ECM components, followed by signal transduction processes and then cytoskeleton assembly. Stellate cells also exist in extrahepatic organs such as pancreas, lung, kidney, and intestine. Hepatic and extrahepatic stellate cells form the stellate cell system.

Process and thermodynamics of ligand–receptor interaction studied using a novel simulation method

A novel simulation method for unbinding a ligand from its receptor is described. It requires no prior knowledge of the unbinding trajectory and has atomic resolution. It places forces of equal magnitude but opposite directions on the two molecules, and lets the system locate an unbinding trajectory. The mutual repulsion method has been applied successfully to the bovine serum retinol-binding protein / retinol complex. A change in water structure has been observed during the unbinding process. The free energy change of unbinding has also been evaluated, and the value compares favourably with the experimental result.

Bioinorganic and bioorganic studies of liver alcohol dehydrogenase

Liver alcohol dehydrogenase (E.C.1.1.1.1) is an NAD +/NADH dependent enzyme with a broad substrate specificity being active on an assortment of primary and secondary alcohols. It catalyzes the reversible oxidation of a wide variety of alcohols to the corresponding aldehydes and ketones as well as the oxidation of certain aldehydes to their related carboxylic acids. Although the bioinorganic and bioorganic aspects of the enzymatic mechanism, as well as the structures of various ternary complexes, have been extensively studied, the kinetic significance of certain intermediates has not been fully evaluated. Nevertheless, the availability of computer-assisted programs for kinetic simulation and molecular modeling make it possible to describe the biochemical mechanism more completely. Although the true physiological substrates of this zinc metalloenzyme are unknown, alcohol dehydrogenase effectively catalyzes not only the interconversion of all- trans-retinol and all- trans-retinal but also the oxidation of all- trans-retinal to the corresponding retinoic acid. Retinal and related vitamin A derivatives play fundamental roles in many physiological processes, most notably the vision process. Furthermore, retinoic acid is used in dermatology as well as in the prevention and treatment of different types of cancer. The enzyme-NAD +-retinol complex has an apparent p K a value of 7.2 and loses a proton rapidly. Proton inventory modeling suggests that the transition state for the hydride transfer step has a partial negative charge on the oxygen of retinoxide. Spectral evidence for an intermediate such as E-NAD +-retinoxide was obtained with enzyme that has cobalt(II) substituted for the active site zinc(II). Biophysical considerations of water in these biological processes coupled with the inverse solvent isotope effect lead to the conclusion that the zinc-bound alkoxide makes a strong hydrogen bond with the hydroxyl group of Ser48 and is thus activated for hydride transfer. Moderate pressure accelerates enzyme action indicative of a negative volume of activation. The data with retinol is discussed in terms of enzyme stability, mechanism, adaptation to extreme conditions, as well as water affinities of substrates and inhibitors. Our data concern all- trans, 9- cis, 11- cis, and 13- cis retinols as well as the corresponding retinals. In all cases the enzyme utilizes an approximately ordered mechanism for retinol–retinal interconversion and for retinal–retinoic acid transformation.

Relation of serum retinol to acute phase proteins and malarial morbidity in Papua New Guinea children

Acute phase proteins (APPs) are associated with malaria-induced hyporetinemia (serum retinol <0.70 micromol/L); however, the degree of the association is not well documented. The association between malaria-induced hyporetinemia and APPs was assessed. In a cross-sectional study, 90 children with serum retinol concentrations from <0.35 to >1.05 micromol/L were selected from children in a clinical trial of vitamin A supplementation. Serum was collected before treatment allocation. Retinol binding protein (RBP) concentrations were determined by radioimmunoassays, and transthyretin, alpha(1)-acid glycoprotein (AGP), alpha(1)-antichymotrypsin, C-reactive protein (CRP), haptoglobin, and albumin concentrations by radial immunodiffusion assays. Children in the subsample had high rates of splenomegaly and Plasmodium-positive blood-smear slides (P < 0.01); AGP (Pearson's r = -0.40, P < 0.001) and CRP (r = -0.21, P = 0.04) were inversely correlated with retinol. The negative APPs RBP, transthyretin, and albumin were positively and significantly associated with retinol. All APPs, except alpha(1)-antichymotrypsin, were significantly correlated with splenomegaly. Of the positive APPs, AGP correlated with CRP (r = 0.37, P < 0.001), indicating chronic inflammation. In a stepwise regression analysis, 73% of retinol's variability was explained by RBP and transthyretin. The model predicted that a 1-SD increase in RBP or transthyretin increases retinol by approximately 0.38 or 0.47 micromol/L, respectively, whereas an equivalent increase in AGP decreases retinol by 0.12 micromol/L. The RBP-transthyretin transport complex of retinol is not altered by inflammation. Positive APPs are useful markers of type and severity of inflammation; however, except for AGP, it is unlikely that they can correct for malaria-induced hyporetinemia.

Molecular mechanisms in the reversible regulation of morphology, proliferation and collagen metabolism in hepatic stellate cells by the three‐dimensional structure of the extracellular matrix

Hepatic stellate cells (vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, Ito cells) exist in the perisinusoidal space of the hepatic lobule and store 80% of the body's retinoids as retinyl palmitate in lipid droplets in the cytoplasm. Under physiological conditions, these cells play pivotal roles in the regulation of retinoid homeostasis; they express specific receptors for retinol-binding protein (RBP), a binding protein specific for retinol, on their cell surface, and take up the complex of retinol and RBP by receptor-mediated endocytosis. However, in pathological conditions such as liver fibrosis, these cells lose retinoids and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan and adhesive glycoproteins. The morphology of these cells also changes from star-shaped stellate cells to that of fibroblasts or myofibroblasts. The three-dimensional structure of ECM components was found to regulate reversibly the morphology, proliferation and functions of hepatic stellate cells. Molecular mechanisms in the reversible regulation of stellate cells by ECM imply cell surface integrin binding to ECM components followed by signal transduction processes and then cytoskeleton assembly.

Structural changes in transthyretin produced by the Ile 84 Ser mutation which result in decreased affinity for retinol-binding protein

The X-ray crystal structure of the transthyretin variant Ile 84 Ser has been determined to 1.7A resolution. The functional form of normal transthyretin is a tetramer, having a cylindrical cavity which binds thyroxine and an exterior binding site for the complex of retinol with retinol-binding protein. The naturally occurring amyloidogenic variant Ile 84 Ser has reduced affinity for retinol-binding protein. The results of this study show that the overall structural homology between the C-alpha atoms of the variant and normal protein is very high with differences mainly in the loop regions, in the vicinity of the substitution, and the ligand binding areas. The known functional differences for the variant (ligand-binding) are correlated with the structural changes observed in the region of the ligand-binding site. The substitution at position 84 results in changes in the shape of the putative site for complexation with retinol binding protein. The substitution site occurs at the interface between two tetrame...

Prealbumin-retinol-binding-protein-retinol complex in hemodialysis patients

In hemodialysis (HD) patients, serum prealbumin (TBPA) is correlated to nutritional status and outcome despite usually elevated serum levels. The purpose of this work was to study the role of TBPA-retinol-binding-protein (RBP)-retinol complex changes in the elevation of serum TBPA in HD patients. Serum TBPA, RBP, and retinol were measured in 30 otherwise healthy HD patients (15 men, 15 women) and in 30 healthy volunteers (15 men, 15 women). The dependence of TBPA on RBP was studied by covariance and regression methods. TBPA (p less than 0.05), RBP (p less than 0.01), and retinol (p less than 0.05) were elevated in HD patients. Elevated TBPA was associated with a decrease of TBPA free from RBP (p less than 0.01). The decrease of free TBPA may explain the reduction of TBPA breakdown and its elevation in HD patients.