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Query: UNIPROT:P06889 (Mol)
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Vitamin A (retinol) deficiency is associated with impaired healing from lung injury in very-low-birth-weight (VLBW) neonates susceptible to bronchopulmonary dysplasia (BPD). Vitamin A supplementation from birth may ameliorate this adverse outcome. We hypothesized that plasma retinol-binding protein (RBP) response to vitamin A administration, which provides a dynamic measure to vitamin A status, might be useful for early recognition of vitamin A deficiency in VLBW neonates at risk for BPD. We prospectively studied 20 VLBW neonates (inclusion criteria: birth weight < 1300 g, gestational age < 30 weeks, need for supplemental oxygen and mechanical ventilation for > 24 h after birth) who were eligible to receive vitamin A supplementation. In addition to sequential assessment of vitamin A status, we measured plasma RBP just before and 3 and 6 h after an intramuscular injection of vitamin A (2000 IU/kg retinyl palmitate) on Postnatal Days 1, 7, 15, 21, 29, and 43. The percentage increase in plasma RBP (delta-RBP) was calculated. A high plasma delta-RBP value ( > 8%) is indicative of vitamin A deficiency. Based on pulmonary outcome, the infants were divided into two groups: BPD (n = 12) and No BPD (n = 8). Mean vitamin A intake ranged from 1414 to 2114 IU/kg/day and did not differ between infant groups. Mean plasma vitamin A concentration increased from baseline levels on Postnatal Day 1 to levels within the desired range of 1.05-2.10 mumol/liter (30.0-60.0 micrograms/dl) during supplementation period in both infant groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Biochem Mol Med 1995 Feb
PMID:Sequential evaluation of plasma retinol-binding protein response to vitamin A administration in very-low-birth-weight neonates. 755 19

Retinoic acid, one of the principle active metabolites of vitamin A (retinol), is believed to be essential for numerous developmental and physiological processes. Vitamin A deprivation (VAD) during development leads to numerous congenital defects. Previous studies of retinoic acid receptor (RAR) deficient mice failed to reveal any of these VAD-induced defects. This finding suggested that either the RARs are functionally redundant or that they are not critically required during development. In order to address these possibilities, we derived a number of RAR compound mutants. Unlike RAR single mutants, these compound null mutants died either in utero or shortly following birth. Histological analysis revealed essentially all of the defects characteristic of fetal VAD. A number of additional malformations, not described in previous VAD studies, were also observed. These included defects of the ocular and salivary glands and their ducts, the skeletal elements of the fore- and hindlimbs, and the cervical region of the axial skeleton. In addition, with the exception of derivatives forming within the first pharyngeal arch, most of the elements derived from mesectoderm emanating from cranial and hindbrain levels were affected. A number of these mutants also exhibited supernumerary cranial skeletal elements characteristics of the reptilian skull. A summary of the defects found in these RAR double mutants is presented.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Developmental roles of the retinoic acid receptors. 762 98

Free retinoids suffer promiscuous metabolism in vitro. Diverse enzymes are expressed in several subcellular fractions that are capable of converting free retinol (retinol not sequestered with specific binding proteins) into retinal or retinoic acid. If this were to occur in vivo, regulating the temporal-spatial concentrations of functionally-active retinoids, such as RA (retinoic acid), would be enigmatic. In vivo, however, retinoids occur bound to high-affinity, high-specificity binding proteins, including cellular retinol-binding protein, type I (CRBP) and cellular retinoic acid-binding protein, type I (CRABP). These binding proteins, members of the superfamily of lipid binding proteins, are expressed in concentrations that exceed those of their ligands. Considerable data favor a model pathway of RA biosynthesis and metabolism consisting of enzymes that recognize CRBP (apo and holo) and holo-CRABP as substrates and/or affecters of activity. This would restrict retinoid access to enzymes that recognize the appropriate binding protein, imparting specificity to RA homeostasis; preventing, e.g. opportunistic RA synthesis by alcohol dehydrogenases with broad substrate tolerances. An NADP-dependent microsomal retinol dehydrogenase (RDH) catalyzes the first reaction in this pathway. RDH recognizes CRBP as substrate by the dual criteria of enzyme kinetics and chemical crosslinking. A cDNA of RDH has been cloned, expressed and characterized as a short-chain alcohol dehydrogenase. Retinal generated in microsomes from holo-CRBP by RDH supports cytosolic RA synthesis by an NAD-dependent retinal dehydrogenase (RalDH). RalDH has been purified, characterized with respect to substrate specificity, and its cDNA has been cloned. CRABP is also important to modulating the steady-state concentrations of RA, through sequestering RA and facilitating its metabolism, because the complex CRABP/RA acts as a low Km substrate.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Enzymes and binding proteins affecting retinoic acid concentrations. 762

Gp15/400 is a surface-proximal antigen of the filarial nematode Brugia malayi, produced as a large polyprotein precursor comprising an array of polypeptide units of approx. 14.5 kDa. Here we describe a biochemical function for gp15/400. A single 14.5-kDa unit of gp15/400 has been expressed in Escherichia coli, and found to dimerise spontaneously. This protein (designated P-RUNG) has high-affinity fatty acid and retinoid binding activity, suggesting that the parent polypeptide itself has these properties. Fluorescent fatty acid probes show significant enhancement of fluorescence intensity and shifts in emission wavelength in the presence of P-RUNG, which can be reversed by competing non-fluorescent fatty acids (oleic, palmitic, steric, arachidonic), retinoids (retinol and retinoic acid) and oleoyl Coenzyme A, but not by tryptophan, cholesterol, caproic acid, squalene, tocopherol, tocopherol acetate, succinyl CoA, 2-methylbutyric acid and 2-methylvaleric acid. Changes in intrinsic fluorescence of retinol or retinoic acid confirmed the retinoid binding function. The results of fluorescence titration experiments are consistent with stoichiometric binding to a single protein site per monomer unit with affinities (Kd) in the range 2 x 10(-6) M (for the fluorescent probe 11-((5-dansyl)amino)undecanoic acid) and 2 x 10(-7) M (for oleic acid). The extreme blue shift of the fluorescent fatty acid-protein complex suggests an unusually low polarity for the protein binding site. The intrinsic fluorescence of the single tryptophan residue of P-RUNG indicates that it also is deeply buried in a non-polar environment, but is probably not involved in ligand binding. Gp15/400, therefore, represents a new class of lipid binding protein which is possibly restricted to nematodes.
Mol Biochem Parasitol 1995 Apr
PMID:The gp15/400 polyprotein antigen of Brugia malayi binds fatty acids and retinoids. 763 Mar 82

P2 myelin protein (P2) and cellular retinol binding protein (CRBP) are members of a family of cellular lipophilic transport proteins. P2 has been refined at a resolution of 2.7 A, and CRBP has been solved by molecular replacement and refined to a resolution of 2.1 A. The members of this family form a compact three-dimensional structure built up from ten antiparallel strands that fold to form an orthogonal barrel containing the ligand. In P2, the carboxylate group of an oleic acid ligand interacts with the side-chains of two arginine (106 and 126), and one tyrosine (128) residues. The ligand adopts a U-shaped conformation. In CRBP, the all-trans-retinol has a planar conformation with its alcohol group hydrogen bonding to the side-chain of glutamine 108 (equivalent to residue 106 in P2). The local interactions of glutamine 108 explain CRBP's preference for binding retinol rather than retinal. The side-chain of lysine 40 makes a close contact with the isoprene tail of the retinol.
J Mol Biol 1993 Apr 20
PMID:Crystallographic studies on a family of cellular lipophilic transport proteins. Refinement of P2 myelin protein and the structure determination and refinement of cellular retinol-binding protein in complex with all-trans-retinol. 768 27

The binding capacity (Cmax) of the glucocorticoid hormone receptor (GR) was affected by vitamin A status in rat liver. In rats fed on a vitamin A-overloaded diet as well as in rats administered with retinoic acid (RA) there was an increased ratio Cmax of nuclear GR (expressed as fmol/mg liver): Cmax of cytosolic GR (expressed as fmol/mg liver) while in rats fed on a vitamin A-deficient diet this ratio was decreased. These results suggested that an increased amount of RA, resulting from either metabolization of an increased amount of dietary retinol or RA administration, enhanced the translocation of GR from the cytosolic compartment to the nuclear compartment. Moreover such an increased amount of RA could also induce the observed decreased Cmax of the total GR that we observed. These observations were similar to the well known effects of dexamethasone administration on the properties of GR. It is probable that RA, similarly to dexamethasone treatment, induces a dissociation of the tetrameric form of the cytosolic GR and thus enhances translocation of the monomeric form from cytosol to nucleus and also resulting in an increased proteolytic degradation of the receptor.
J Steroid Biochem Mol Biol 1995 Apr
PMID:Retinoids modulate the binding capacity of the glucocorticoid receptor and its translocation from cytosol to nucleus in liver cells. 773 99

The interactions with retinol and retinol analogs of bovine cellular retinol-binding protein (CRBP) have been investigated, by means of fluorescence titrations, to obtain more information on the structural features of retinoid that may be required for their interaction with the binding protein. An approximately stoichiometric binding of retinol to bovine CRBP (K'd approximately 2 nM) has been found in direct binding assays. Although retinal exhibited relatively high binding affinity to bovine CRBP (K'd approximately 30 nM), a large excess of the retinoid could not compete with retinol for the carrier protein. On the assumption that retinol and retinal interact with the same binding site, this result indicates that the above-mentioned apparent dissociation constant for retinol.CRBP may be an overestimate and that its value may be as low as 0.1 nM. The finding of an exceedingly tight binding of retinol to CRBP provides further support for the possible role of CRBP-bound retinol, rather than its uncomplexed labile form, as substrate of enzymes involved in the metabolism of the vitamin. The results of these and previous studies indicate that CRBP is particularly sensitive to modifications of the retinol hydroxyl end group. Axerophthene, a retinol analog bearing a hydrogen atom in place of the hydroxyl end group, and beta-ionone exhibit rather low binding affinities for CRBP (K'd approximately 0.2 microM and approximately 4 microM, respectively), suggesting that the hydroxyl group and isoprene tail moieties contribute substantially to the retinol-binding affinity and specificity. These findings are consistent with the indications emerging from the three-dimensional structure determination of retinol.CRBP [Cowan, S. W., Newcomer, M. E. & Jones, T. A. (1993) J. Mol. Biol. 230, 1225-1246]. Additionally, the bulky end groups of fenretinide and N-ethyl retinamide replacing the retinol hydroxyl group have been found to prevent retinoid binding to CRBP. The primary structure of bovine CRBP has been determined and is highly similar to the structures of both human and rat CRBP (97% and 95% identical, respectively).
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PMID:Interactions with retinol and retinoids of bovine cellular retinol-binding protein. 774 71

The crystal structure of the complex between the 50 kDa metallo-endoproteinase from Serratia marcescens (SMP), a member of the metzincin superfamily, and an inhibitor from Erwinia chrysanthemi (Inh) was solved by molecular replacement using the known structure of SMP, and refined at 2.30 A resolution to a crystallographic R-factor of 0.195. The E. chrysanthemi inhibitor folds into a compact eight-stranded antiparallel beta-barrel of simple up-down topology such as is found for members of the retinol binding protein family. It mainly interacts with the protease via its five N-terminal residues, which insert into the active site cleft, occupying the S' sites. The first N-terminal residue, SerI1, is partially cleaved off by the protease, while SerI2 makes a hydrogen bond with the catalytically active glutamic acid, Glu177, of the protease. Further interactions are made between one face of the inhibitor formed by the strands s3, s4 and s5 and the protease segment 218 to 228, which is located immediately after the characteristic "Met-turn" of the metzincins.
J Mol Biol 1995 May 05
PMID:Crystal structure of a complex between Serratia marcescens metallo-protease and an inhibitor from Erwinia chrysanthemi. 775 31

Alcohol metabolism may result in oxidant stress and free radical injury through a variety of mechanisms. Lovastatin may also produce oxidant stress by reducing levels of an endogenous antioxidant, coenzyme Q (CoQ). The separate and combined effects of ethanol, 20 EN% in a total liquid diet, and lovastatin, 67 mg/kg diet, on alpha-tocopherol, retinol palmitate, CoQ9 and thiobarbituric acid reactive (TBAR) material in liver from rats were determined. The effect of exogenous CoQ10 on these treatment groups was also determined. Food consumption, weight gain, liver lipid and TBAR material were similar between treatment groups. Compared to control animals, ethanol reduced retinol palmitate significantly, from 143 to 90 micrograms/g wet weight. Lovastatin had no effect on retinal palmitate nor did it act additively with ethanol. Ethanol decreased liver alpha-tocopherol from 28 to 12 micrograms/g wet weight and lovastatin diminished it to 12 micrograms; no additive effect was evident. Ethanol had no effect, but lovastatin decreased CoQ9 from 83 to 55 micrograms/g wet weight. Supplementation with CoQ10 did not modulate the effect of ethanol on retinal palmitate, but it did reverse the effect of lovastatin on CoQ9. Supplementary CoQ10 did not alter control levels of alpha-tocopherol, but it appeared to reverse most of the decrease in alpha-tocopherol attributable to ethanol or lovastatin separately. It only partially reversed the effect of ethanol and lovastatin combined on alpha-tocopherol, however. As expected, lovastatin had no effect on CoQ10 levels in supplemented animals. Ethanol, either separately or in combination with lovastatin, diminished liver stores of CoQ10 by almost 40%. We conclude that 20 EN% ethanol given in a liquid diet for 5 weeks is sufficient to lower retinol palmitate and that lovastatin reduces CoQ9. Both diminish alpha-tocopherol, an effect largely overcome by CoQ10 supplementation with either drug alone, but not with the combination. Since many individuals chronically consume the levels of ethanol represented by this experiment, and since a certain number of those also take lovastatin, further research into the possible clinical significance of these observations is warranted.
Mol Aspects Med 1994
PMID:Effects of ethanol, lovastatin and coenzyme Q10 treatment on antioxidants and TBA reactive material in liver of rats. 775 31

Testicular peritubular cells produce a paracrine factor termed PModS that mediates mesenchymal-epithelial interactions and modulates Sertoli cell functions essential for the process of spermatogenesis. Sertoli cells produce lactate as a preferred energy metabolite for developing spermatogenic cells. The current study was designed to examine the actions of PModS and hormones on Sertoli cell lactate production at various stages of pubertal development. Sertoli cells were isolated from pre-pubertal (10 day), mid-pubertal (20 day) and late pubertal (35 day) rat testes. Lactate accumulation in the conditioned-medium of cultured Sertoli cells was measured. Basal lactate production increased approximately fivefold during pubertal Sertoli cell development. Therefore, lactate production increases as the Sertoli cell differentiates during pubertal development. The ability of regulatory agents such as FSH or a combination of FSH, insulin, retinol and testosterone (FIRT) to stimulate lactate production decreased during pubertal development as Sertoli cell differentiation increased. Purified PModS stimulated lactate production in Sertoli cell preparations throughout pubertal development. PModS had a greater effect than FSH in stimulating late pubertal Sertoli cell lactate production. PModS in combination with FIRT resulted in an additive stimulation of lactate production suggesting a distinct mechanism of action for PModS. Observations support the proposal that the locally produced paracrine factor PModS mediates mesenchymal-epithelial cell interactions during pubertal development and that these interactions promote Sertoli cell differentiated functions (i.e. lactate production) required for the developing spermatogenic cells.
Mol Cell Endocrinol 1994 Aug
PMID:Developmental regulation of Sertoli cell lactate production by hormones and the testicular paracrine factor, PModS. 782 7


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