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PubMed1993

Aspartimide formation in the joining peptide sequence of porcine and mouse pro-opiomelanocortin.

The joining peptide (JP) portion of pro-opiomelanocortin extracted from mouse pituitary glands has previously been shown to exist in one major and several distinct minor forms (Bennett, H. P. J. (1986) Peptides 7, 614-622). We now confirm the heterogeneous nature of JP extracted from mouse neurointermediate pituitary glands and show that similar forms of JP are also to be found in extracts of porcine pituitary glands. Three forms of porcine JP (pJP-A, pJP-B, and pJP-C) were purified from whole porcine pituitary glands using reversed-phase high performance liquid chromatography methods. The three structural variants constitute approximately 10, 75, and 15%, respectively, of the total JP observed. Mass spectrometric analysis revealed that pJP-C was 18 mass units smaller than pJP-B, which is consistent with the formation of a succinimide structure at the aspartyl 16-glycine 17 peptide bond. Such symmetrical imide structures are known to hydrolyze at physiological pH to yield a mixture of the original alpha-aspartyl peptides and isomerized isoaspartyl peptides. We were able to show that pJP-A was the isomerized isoaspartyl form by demonstrating that pJP-A but not pJP-B was a substrate for the protein carboxyl methyltransferase enzyme (L-isoaspartyl/D-aspartyl protein methyltransferase; EC 2.1.1.77) purified from bovine erythrocytes. This cytosolic enzyme is known to preferentially methylate L-isoaspartyl residues within model substrates. Control experiments in which JP was incubated in the acidic medium used to extract the pituitary tissue showed that the isoforms of pJP are not artifacts of peptide purification. Furthermore, we have isolated the isoforms of pJP at levels which are 100 times greater than would be expected for a spontaneous reaction. We conclude that the formation of the aspartimide form of JP appears to be a facilitated process, possibly occurring as a result of conformation constraints dictated by the structure of pro-opiomelanocortin, or an as yet uncharacterized post-translational event.

Adrenocorticotropic Hormone↗

PubMed1981

A possible variant of thyroxine-binding globulin in Australian Aborigines.

We have recently described a major variation from the normal levels of serum thyroxine-binding globulin in many Australian Aborigines [1]. Subsequently we presented evidence that affected individuals were widely distributed throughout Australia, that "low values of thyroxine-binding globulin were not caused by environmental or health factors, but were inherited in an autosomal dominant fashion [2]. Refetoff [3] has shown that the cause of genetically determined low thyroxine-binding globulin levels in Caucasians is alteration in synthesis rate without any structural variation of the protein. Since however the "low" thyroxine-binding globulin of Aborigines is vastly more prevalent and genetically distinct from the X-linked type, we investigated the possibility that this may be a structural variant. Evidence suggestive of this includes results from heat inactivation, competitive binding of thyroxine to thyroxine-binding globulin to measure affinity, and use of a radioimmunoassay different from that used in the original work. The "Low thyroxine-binding globulin of Aborigines may be a protein with a structural variation at or near the binding site for thyroxine, resulting in low affinity for thyroxine and hence "low" results with assay methods which depend upon the thyroxine binding site. Since the Australoid peoples, to whom Australian Aborigines are racially related, are distributed widely throughout the southern hemisphere it is important to establish whether this variant is found outside Australia in order to avoid the likelihood of misdiagnosis of thyroid disease in such subjects.

Australia↗

PubMed2005

Structural and enzymatic parameters that determine alkyl dehydrogenation/hydroxylation of capsaicinoids by cytochrome p450 enzymes.

Previous studies on the metabolism of capsaicinoids, natural products isolated from chili peppers, demonstrated the production of unique macrocyclic, alkyl dehydrogenated, omega-, and omega-1-hydroxylated products. This study investigated the structural and enzymatic parameters that direct selective alkyl dehydrogenation and hydroxylation of capsaicinoids, using a variety of structurally related capsaicinoid analogs and cytochrome P450 (P450) enzymes. CYP2C9 preferentially catalyzed alkyl dehydrogenation, whereas CYP2E1 and 3A4 catalyzed omega- and omega-1-hydroxylation, respectively. Analysis of incubations containing various P450s and structural variants of capsaicin by liquid chromatography-tandem mass spectrometry demonstrated similarities in the rate of capsaicinoid metabolism, but marked differences in the metabolite profiles. Production of macrocyclic and omega-1-hydroxylated metabolites from the various capsaicinoids was dependent on the structure of the alkyl terminus and P450 enzyme. A tertiary carbon at the omega-1 position, coupled to an adjacent unsaturated bond at the omega-2,3 position, enhanced the formation of the macrocyclic and dehydrogenated metabolites and were requisite structural features for omega-1-hydroxylated product formation. Conversely, substrates lacking these structural features were efficiently oxidized to the omega-hydroxylated metabolite. These data were consistent with our hypothesis that metabolism of the alkyl portion of capsaicinoids was governed, in part, by the stability and propensity to form an intermediate radical and a carbocation, and a direct interaction between the alkyl terminus and the heme of many P450 enzymes. These results provided valuable insights into potential mechanisms by which P450s metabolize capsaicinoids and highlight critical chemical features that may also govern the metabolism of structurally related compounds including fatty acids, monoter-penes, and isoprenoids.

Capsaicin↗

PubMed1991

Cell type-specific integrin variants with alternative alpha chain cytoplasmic domains.

The integrin heterodimers composed of the alpha 6 subunit with the beta 1 or beta 4 subunit (alpha 6 beta 1 and alpha 6 beta 4) are receptors for laminin and basement membrane components, respectively. The alpha 3 beta 1 integrin recognizes laminin, collagen, fibronectin, or epiligrin. We report the identification of structural variants (A and B) of the alpha 6 and alpha 3 subunits, containing distinct cytoplasmic domains. The expression of one cytoplasmic domain or the other, based probably on alternative exon usage, is cell-type dependent. Most transformed cell lines express both alpha 6A and alpha 6B isoforms, as determined by mRNA amplification or antibody immunoprecipitation. In contrast, embryonic fibroblasts express exclusively alpha 6A, and embryonic stem cells express exclusively alpha 6B. In most normal tissues, both alpha 6 isoforms are detectable, but several tissues express either alpha 6A or alpha 6B. The alpha 3B mRNA was amplified from heart and brain, while all other tissues and cell lines tested contained only alpha 3A mRNA. Alternative cytoplasmic domains may provide a means for varying the cellular responses to the ligands of alpha 6 and alpha 3 integrins according to the cell type.

Amino Acid Sequence↗

PubMed1996

Exon/intron structure of the human ALL-1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias.

The acute lymphoblastic leukaemia (ALL)-1 gene on human chromosome 11q23 is the site of many locally clustered chromosomal alterations associated with several types of acute leukaemias, including deletions, partial duplications and translocations. Structurally variant proteins derived from the altered gene presumably cause the malignant transformation of early haemopoietic progenitor cells. According to previously published reports, the gene consisted of at least 21 exons spread over approximately 100 kb. In this report a set of genomic fragments was isolated that represent a total of 35 exons (exons 3-37) encompassing > 95% of the protein-coding region (except exons 1 and 2) and the 3'-non-translated region of the gene. The distances between these exons were determined and a detailed restriction map was produced. The majority of the exon/intron boundaries were sequenced and an intron-phase analysis was performed. The results form the basis for a greater understanding of the translocations and other structural alterations of the gene that conserve the open reading frame and thus produce presumably oncogenic variants of the ALL-1 protein.

Base Sequence↗

PubMed2004

Two-step synthesis of carbohydrates by selective aldol reactions.

Studies of carbohydrates have been hampered by the lack of chemical strategies for the expeditious construction and coupling of differentially protected monosaccharides. Here, a synthetic route based on aldol coupling of three aldehydes is presented for the de novo production of polyol differentiated hexoses in only two chemical steps. The dimerization of alpha-oxyaldehydes, catalyzed by l-proline, is then followed by a tandem Mukaiyama aldol addition-cyclization step catalyzed by a Lewis acid. Differentially protected glucose, allose, and mannose stereoisomers can each be selected, in high yield and stereochemical purity, simply by changing the solvent and Lewis acid used. The reaction sequence also efficiently produces (13)C-labeled analogs, as well as structural variants such as 2-amino- and 2-thio-substituted derivatives.

Acids↗

PubMed1991

Secondary structure of coliphage Q beta RNA. Analysis by electron microscopy.

The secondary structure of genomic RNA from the coliphage Q beta has been examined by electron microscopy in the presence of varying concentrations of spermidine using the Kleinschmidt spreading technique. The size and position of structural features that cover 70% of the viral genome have been mapped. The structural features that are visualized by electron microscopy in Q beta RNA are large. They range in size from 170 to 1600 nucleotides. A loop containing approximately 450 nucleotides is located at the 5' end of the RNA. It includes the initiation region for the viral maturation protein. A large hairpin containing approximately 1600 nucleotides is located in the center of the molecule. It is multibranched and includes most of the viral coat gene, the readthrough region of the A1 gene, and approximately one third of the viral replicase gene. Within the central hairpin, the initiation region for the viral replicase gene pairs with a region within the distal third of the viral coat gene. This structure may participate in the regulation of translational initiation of the viral replicase gene. Two structural variants of the central hairpin were observed. One of them brings the internal S and M viral replicase binding regions into juxtaposition. These observations suggest that the central hairpin may also participate in the regulation of translation of the viral coat gene. The secondary structures that are observed in Q beta RNA differ significantly from structures that we described previously in the genomic RNA of coliphage MS2 but are similar to structures we observed by electron microscopy in the related group B coliphage SP.

Coliphages↗

PubMed1995

[Topography of the hypophysis and its neighboring structures].

The first part of the article informs about four points: the skeletal structures of the middle cranial fossa, the basic divisions of the gland and their connections with the hypothalamus, its blood supply, and its development. The topographic part deals with the incorporation of the pituitary gland in the sella turcica, its relationship to the meninges, the subarachnoid cavity and other neighbouring structures, especially the sphenoidal sinus, the posterior ethmoidal cells as well as the chiasma opticum. With respect to the latter, the position of the fibres in the optic nerve, chiasma and optic tract and the consequences of lesions in characteristic areas are described. Finally, the variant structures of the cavernous sinus and the topography of its contents are discussed. Detailed data can be found about the course of the oculomotor nerves and the possible locations of their lesions.

Cavernous Sinus↗

PubMed2004

Evaluation of styloid process by three-dimensional computed tomography.

The purpose of this paper was to investigate the length, medial angulations and other structural variants of the styloid process (SP) by three-dimensional computed tomography (3D CT) in patients without any complaints related to elongated SP. We performed temporal computed tomography (CT) scans in 138 cases (87 males, 51 females) with a mean age of 34.5 (17-86). The structure, length and medial angulation of SPs were evaluated on 3D reconstructed images. SP lengths varied between 1.58 and 5.48 cm (average length 2.83 cm), and the angles varied between 60.6 and 84.1 degrees (average angle 69.4 degrees). Other morphological findings were absence of SP (3 unilateral and 1 bilateral), ossification of stylohyoid ligament (9 unilateral and 27 bilateral), irregular SP (5 unilateral and 5 bilateral), fragmentation of SP (12 unilateral and 9 bilateral), absence of the proximal part (5 unilateral and 9 bilateral) and double proximal part (1 unilateral). According to our results, we propose a new classification. Absence of SP, absence of the proximal part of SP, duplication of the proximal part of SP and angle values of SP have never been reported before according to the available medical literature. 3D CT is an effective method in the evaluation of the SP length, angulations and other morphological characteristics.

Adolescent↗

PubMed1995

Genetic variations in human testosterone-estradiol binding globulin.

The human testosterone-estradiol-binding globulin (hTeBG) is a plasma heterogeneous glycoprotein with high affinity for a number of circulating steroid hormones. The heterogeneity originates from differential glycosylation of a common protein precursor. Analysis of desialylated hTeBG by isoelectric focusing (IEF) has revealed that microheterogeneity could be partly attributed to variability in sialic acid content or rearrangement of amino acid composition. We have studied this possibility by the analysis of desialylated serum hTeBG by Western blotting of proteins previously separated on IEF-gels. Two distinct well-defined IEF patterns were identified. The most frequent consisted of two major IEF-bands of equal color intensity. The other pattern consisting of four IEF-bands was present in only 5.55% of the total serum samples analyzed. Family studies showed that these phenotypes were autosomally inherited with a simple Mendelian transmission and allele frequencies had an excellent agreement between the observed and expected phenotypes. Androgen affinity constants and serum concentrations of hTeBG variant were similar to those of normal hTeBG. Molecular analyses of each of the exons of hTeBG gene by denaturing gradient gel electrophoresis revealed the presence of a point mutation in exon 8. The studies presented herein confirm and extend previous reports on the existence of structural variants of hTeBG. In addition, the mutation reported in this study is probably the same as that recently identified within numerous ethnic groups throughout the world, thus further supporting the concept of a two allele gene worldwide concoding hTeBG.

Female↗

PubMed1988

An isoelectricfocusing method to detect hemoglobin variants in newborn blood samples including the beta-thalassemias.

An isoelectricfocusing method has been developed to enable large scale screening of newborn blood for hemoglobinopathies. The method utilizes a thin layer agarose gel containing carrier ampholytes in the pH range 6-8. The gradient is non linear allowing increased resolution in the pH region 6.8-7.8 where most hemoglobin variants are isoelectric. The increased resolution between Hb A and Hb Fac enables screening for beta-thalassemia by densitometric analysis. By calculating the ratio of Hb A/Hb Fac or Hb F/Hb A it is possible to detect newborns heterozygous for beta(+)- or beta(0)-thalassemia. Structural variants, unresolved by other electrophoretic methods, are easily detected. Seventy-two samples can be analyzed on a single gel in 90 minutes. Traces of hemoglobin variants can be detected by a heme-specific stain requiring no destain step.

Fetal Blood↗

PubMed1981

[Karyotypic structure of Chinese hamster clone cell populations in prolonged culture].

The Karyotypic structure of some clones and subclones of Chinese hamster cells has been studied (CHO-KI). 60-80% of all the clonal cells demonstrated the identical karyotype (the main structural variant of karyotype - MSVK). The distribution of cells according to the number of chromosomes does not vary within 90 passages of clone cultivation (about 300 cell generations) and 35 passages of subclone cultivation (more than 100 cell generations). In two of three clones the frequencies of cells with MSVK and with additive karyotype variants do not change, while in one clone a long cultivation leads to lowering the frequency of cells with MSVK and to growing the frequency of cells with other karyotype variants. Recloning does not lead to decreasing the karyotypic heterogeneity of clonal populations. The distribution of clonal cells according to the deviation from the modal number of chromosomes is closely related to the Poisson distribution, while the distributions of cells from two clones with the stable karyotypic structure according to the number of greater structural greater deviations from MSVK are related to a degeneration Poisson distribution. Different chromosomes are involved in karyotypic changes in variable proportions, and the frequencies of cells with simultaneous deviations in various chromosome groups are in most instances higher than frequencies expected in the case of independent deviations. The reasons of stability of karyotypic structure in clonal populations is discussed.

Animals↗

PubMed1988

A platelet disorder due to a structural abnormality of membrane glycoprotein Ib.

In a patient with mild bleeding symptoms, decreased platelet spreading and defective aggregation, an abnormal membrane glycoprotein (GP) was detected. Staining and surface labelling characteristics, cleavage by calcium-activated protease and decreased content of normal GP Ib in the platelets of the patient and 3 related carriers of the abnormal glycopeptide suggest that the additional component is a genetic GP Ib variant structurally characterized by an increase of about 20,000 in apparent Mr of the large subunit GP Ib alpha. The observed hereditary membrane GP abnormality although present in heterozygous state may be causally related to the defect of platelet function.

Adult↗

PubMed1998

An evolutionary approach to the design of glutathione-linked enzymes.

Studies of protein structure provide information about principles of protein design that have come into play in natural evolution. This information can be exploited in the redesign of enzymes for novel functions. The glutathione-binding domain of glutathione transferases has similarities with structures in other glutathione-linked proteins, such as glutathione peroxidases and thioredoxin (glutaredoxin), suggesting divergent evolution from a common ancestral protein fold. In contrast, the binding site for glutathione in human glyoxalase I is located at the interface between the two identical subunits of the protein. Comparison with the homologous, but monomeric, yeast glyoxalase I suggests that new domains have originated through gene duplications, and that the oligomeric structure of the mammalian glyoxalase I has arisen by 'domain swapping'. Recombinant DNA techniques are being used for the redesign of glutathione-linked proteins in attempts to create binding proteins with novel functions and catalysts with tailored specificities. Enzymes with desired properties are selected from libraries of variant structures by use of phage display and functional assays.

Binding Sites↗

PubMed1997

Characterization of a structurally and functionally diverged acyl-acyl carrier protein desaturase from milkweed seed.

A cDNA for a structurally variant acyl-acyl carrier protein (ACP) desaturase was isolated from milkweed (Asclepias syriaca) seed, a tissue enriched in palmitoleic (16:1delta9)* and cis-vaccenic (18:1delta11) acids. Extracts of Escherichia coli that express the milkweed cDNA catalyzed delta9 desaturation of acyl-ACP substrates, and the recombinant enzyme exhibited seven- to ten-fold greater specificity for palmitoyl (16:0)-ACP and 30-fold greater specificity for myristoyl (14:0)-ACP than did known delta9-stearoyl (18:0)-ACP desaturases. Like other variant acyl-ACP desaturases reported to date, the milkweed enzyme contains fewer amino acids near its N-terminus compared to previously characterized delta9-18:0-ACP desaturases. Based on the activity of an N-terminal deletion mutant of a delta9-18:0-ACP desaturase, this structural feature likely does not account for differences in substrate specificities.

Acyl Carrier Protein↗

PubMed1985

Biochemical characterisation of A blood group activity on human platelets.

A butanol extraction procedure has been used to isolate the blood group A antigen determinants from platelet membranes and to determine their biochemical structure-glycolipid and/or glycoprotein. The blood group A serological activity was found to reside entirely in the butanol (organic) fraction. When this fraction was analyzed by thin-layer chromatography, the A-inhibitory activity was found to comigrate with extracts of erythrocyte type Aa, Ab and Ac variant structures. The results of this study indicate that the ABO blood group A determinants on human platelets are glycolipid, similar in structure to glycolipid A determinants on erythrocytes.

ABO Blood-Group System↗

PubMed2001

Molecular recognition of pyr mRNA by the Bacillus subtilis attenuation regulatory protein PyrR.

The pyrimidine nucleotide biosynthesis (pyr) operon in Bacillus subtilis is regulated by transcriptional attenuation. The PyrR protein binds in a uridine nucleotide-dependent manner to three attenuation sites at the 5'-end of pyr mRNA. PyrR binds an RNA-binding loop, allowing a terminator hairpin to form and repressing the downstream genes. The binding of PyrR to defined RNA molecules was characterized by a gel mobility shift assay. Titration indicated that PyrR binds RNA in an equimolar ratio. PyrR bound more tightly to the binding loops from the second (BL2 RNA) and third (BL3 RNA) attenuation sites than to the binding loop from the first (BL1 RNA) attenuation site. PyrR bound BL2 RNA 4-5-fold tighter in the presence of saturating UMP or UDP and 150- fold tighter with saturating UTP, suggesting that UTP is the more important co-regulator. The minimal RNA that bound tightly to PyrR was 28 nt long. Thirty-one structural variants of BL2 RNA were tested for PyrR binding affinity. Two highly conserved regions of the RNA, the terminal loop and top of the upper stem and a purine-rich internal bulge and the base pairs below it, were crucial for tight binding. Conserved elements of RNA secondary structure were also required for tight binding. PyrR protected conserved areas of the binding loop in hydroxyl radical footprinting experiments. PyrR likely recognizes conserved RNA sequences, but only if they are properly positioned in the correct secondary structure.

Bacillus subtilis↗

PubMed1991

Straight and paired helical filaments in Alzheimer disease have a common structural unit.

The presence of abundant neurofibrillary tangles in certain areas of the brain constitutes one of the defining pathological characteristics of Alzheimer disease. The predominant component of the tangle is an abnormal fibrous assembly known as the paired helical filament (PHF). The PHF is formed by a twisted double-helical ribbon of subunits that gives rise to an image alternating in width between 8 nm and 20 nm with a cross-over spacing of 80 nm. Also found in tangles is the straight filament (SF), a different kind of abnormal filament, about 15 nm wide, that does not exhibit the marked modulation in width shown by the PHF. It is reported herein that PHFs and SFs form hybrid filaments displaying both morphologies, that PHFs and SFs share surface epitopes, and that computed maps reveal a similar C-shaped morphological unit in PHFs and SFs, though differing in relative arrangement in the two types of filament. The observations imply that the SF is a structural variant of the PHF and establish a common unit of assembly for these two pathological filaments.

Alzheimer Disease↗