Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transfer of bloodstream-form Trypanosoma brucei variant 221a from calf serum to dog serum-based medium induces acute iron starvation, as the transferrin receptor (Tf-R) of variant 221a binds dog Tf poorly. We show here that transfer to dog serum induces a 3-5-fold increase in Tf-R mRNA and protein within one doubling time (8 h). Because iron stores are still high 8 h after transfer, we infer that the signal for Tf-R overproduction is the decreased availability of cytosolic iron when cellular iron import drops. Up to 30% of the extra Tf-R spills out of the flagellar pocket onto the pellicular surface. Because the 5-fold increase in Tf-R is accompanied by a 5-fold increase in bovine Tf uptake, the up-regulation of Tf-R levels in response to Tf starvation helps the trypanosome to compete for limiting amounts of Tf. We noted that Tf-R levels also vary in calf serum medium. Cells in dense cultures contain up to 5-fold more Tf-R mRNA and protein than in dilute cultures. Only one-tenth of the extra Tf-R reaches the pellicular surface. The increase cannot be explained by a lack of Tf or to cell density sensing but is due to pericellular hypoxia. Our results show that bloodstream-form trypanosomes can regulate the expression of the two Tf-R subunit genes and the localization of their gene products in a flexible manner. This flexibility is made possible by the promoter-proximal position of the two genes in the variant surface glycoprotein expression site.
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PMID:Factors affecting the level and localization of the transferrin receptor in Trypanosoma brucei. 1526 9

Alanine is the most effective precursor for gluconeogenesis among amino acids and the initial reaction is catalyzed by alanine aminotransferases (AlaATs). It is a less extensively studied enzyme under starvation and known to that the enzyme activity increases in liver under starvation. The present study describes the purification and characterization of two isoforms of alanine aminotransferases from starved male rat liver under starvation. The molecular mass of isoforms was found to be 17.7 and 112.2 kDa with isoelectric points of 4.2 and 5.3 respectively for AlaAT I and AlaAT II. Both the enzymes showed narrow substrate specificity for L-alanine with different Km for alanine and 2-oxoglutarate. Both the enzymes were glycoprotein in nature. Inhibition, modification and spectroscopic studies showed that both PLP and free-SH groups are directly involved in the enzymatic catalysis. PLP activated both the enzymes with a Km 0.057 mM and 0.2 mM for AlaAT I and II respectively.
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PMID:Isolation and characterization of cytosolic alanine aminotransferase isoforms from starved rat liver. 1566 81

The structure of several lysosomal membrane glycoproteins (lamp1, lamp2, limpI and limpII) has been described. The significance of the receptor glycoprotein lamp2a in the chaperone-mediated autophagy of cytosolic proteins with KFERQ motif has been described in details as well as the chaperone protein Hsc73 and other chaperones involved in this process. Several modulatory mechanisms of the chaperone-mediated autophagy, which is activated in condition of stress and starvation, were also outlined.
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PMID:[Lysosomal membrane glycoprotein lamp2a--receptor for chaperone-mediated degradation of cytosolic proteins]. 1620 46

Three cDNA clones coding for the contact site A (csA) protein, a cell adhesion molecule of Dictyostelium discoideum, were isolated by screening a cDNA library with monoclonal antibodies. Two of these clones contained the complete coding region for the csA protein of 1542 bp including a sequence of 57 bp coding for the leader. The N terminus of the mature protein, as it was published previously, was identified in the amino acid sequence derived from both full-length cDNA clones. Southern blot analysis suggests the presence of only one csA gene in the haploid genome. Accumulation of the csA-specific message of 1.9 kb begins during development on nitrocellulose filters at 9 h of starvation, and reaches a maximum at 12 h, the time of cell aggregation. Expression of the csA glycoprotein follows closely accumulation of the transcripts. In the multicellular slug stage following cell aggregation, the amount of csA transcripts rapidly declines to low levels.
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PMID:Complete sequence and transcript regulation of a cell adhesion protein from aggregating Dictyostelium cells. 1645 89

Phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 is the major regulatory step in the initiation of protein synthesis in mammals. P67, a cellular glycoprotein, protects phosphorylation of eIF2alpha from kinases. Previously, we reported that the D6/2 mutant of p67 has higher levels of protection of eIF2alpha phosphorylation (POEP) activity. In this study, we report that the D6/2 mutant and its double mutants containing second-site alanine substitutions at the five conserved amino acid residues (D251, D262, H331, E364, and E459) show increased POEP activity in serum-starved rat tumor hepatoma cells. Serum-restoration to those cells did not abolish their increased POEP activity except the D6/2+H331A double mutant. The latter mutant shows slight inhibition of POEP activity during serum starvation and this inhibition increased significantly during serum restoration. KRC-7 cells constitutively expressing the D6/2 mutant showed slightly decreased levels of PKR phosphorylation and significantly low level of phosphorylation of ERKs 1 and 2. The D6/2 mutant also showed increased binding with eIF2alpha and eIF2gamma and almost similar binding with ERKs 1 and 2 as compared to wild type p67. Altogether, our data demonstrate that the increased binding of the D6/2 mutant with the subunits of eIF2 may be in part the cause for its high POEP activity.
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PMID:The binding between p67 and eukaryotic initiation factor 2 plays important roles in the protection of eIF2alpha from phosphorylation by kinases. 1684 28

Galactose metabolism is essential for the survival of Trypanosoma brucei, the etiological agent of African sleeping sickness. T. brucei hexose transporters are unable to transport galactose, which is instead obtained through the epimerization of UDP-glucose to UDP-galactose catalyzed by UDP-glucose 4'-epimerase (galE). Here, we have characterized the phenotype of a bloodstream form T. brucei galE conditional null mutant under nonpermissive conditions that induced galactose starvation. Cellular levels of UDP-galactose dropped rapidly upon induction of galactose starvation, reaching undetectable levels after 72 h. Analysis of extracted glycoproteins by ricin and tomato lectin blotting showed that terminal beta-d-galactose was virtually eliminated and poly-N-acetyllactosamine structures were substantially reduced. Mass spectrometric analysis of variant surface glycoprotein confirmed complete loss of galactose from the glycosylphosphatidylinositol anchor. After 96 h, cell division ceased, and electron microscopy revealed that the cells had adopted a morphologically distinct stumpy-like form, concurrent with the appearance of aberrant vesicles close to the flagellar pocket. These data demonstrate that the UDP-glucose 4'-epimerase is essential for the production of UDP-galactose required for galactosylation of glycoproteins and that galactosylation of one or more glycoproteins, most likely in the lysosomal/endosomal system, is essential for the survival of bloodstream form T. brucei.
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PMID:Galactose starvation in a bloodstream form Trypanosoma brucei UDP-glucose 4'-epimerase conditional null mutant. 1709 69

ADAMTS-like 2 (ADAMTSL2), is a secreted protein resembling the ancillary domains of the ADAMTS proteases, but with distinct structural features. It has 7 thrombospondin type-1 repeats (TSRs), but an unusually long spacer module, which in both humans and mice, contains a novel insertion bearing six N-glycosylation sites. The ADAMTSL2 protein expressed in HEK293F and COS-1 cells, is a cell-surface and extracellular matrix binding glycoprotein, with N-linked carbohydrate constituting approximately 20% by mass. The 4.0 kb Adamtsl2 mRNA is found most abundantly in adult mouse liver, lung and spleen by northern blotting. During mouse embryogenesis, Adamtsl2 was expressed most strongly in the third week of gestation. Adamtsl2 mRNA was detected by in situ hybridization in developing skeletal muscle, liver, bronchial and arterial smooth muscle, skin, intervertebral disc, perichondrium, pancreas and spinal cord. Immunohistochemical localization of ADAMTSL2 protein was similar to mRNA expression. Detection of Adamtsl2 mRNA and protein in developing skeletal myotubes, but not undifferentiated myogenic precursors led us to investigate its regulation during in vitro myogenic differentiation. In C2C12 and 23A2 myogenic cells, but not in 23A2 cells rendered non-myogenic by expression of G12V:H-Ras (9A2 cells), differentiation induced by serum starvation triggered expression of Adamtsl2 mRNA, coordinately with Myog, a marker of muscle differentiation. Furthermore, activation of the key myogenic determinant MyoD in 10T1/2 fibroblasts also triggered expression of Adamtsl2 mRNA. Collectively, the data suggest that induction of Adamtsl2 mRNA is an integral feature of myogenesis.
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PMID:ADAMTS-like 2 (ADAMTSL2) is a secreted glycoprotein that is widely expressed during mouse embryogenesis and is regulated during skeletal myogenesis. 1750 43

Various starvation conditions cause adhesive growth of haploid cells or pseudohyphae formation of diploid cells of Saccharomyces cerevisiae. For the genetic Sigma1278b background, these morphological changes depend on the expression of the gene encoding the cell wall glycoprotein Flo11p, which is increased during nutritional limitations. Deletion of the genes encoding the transcriptional coactivators Rsc1p or Gcn5p impairs FLO11 transcription, which consequently leads to a loss of both haploid invasive growth and diploid pseudohyphae development upon glucose and nitrogen limitation, respectively. In contrast, amino acid starvation induces FLO11-dependent adhesive growth of the rsc1Delta and gcn5Delta strains although FLO11 transcription remains very low. The double deletion strain rsc1Deltaflo11Delta, however, does not grow adhesively, suggesting that the adhesion of the rsc1Delta strain at amino acid starvation is still FLO11-dependent. The FLO11prom-lacZ-encoded beta-galactosidase activities of the rsc1Delta and gcn5Delta mutant strains increase manifold upon amino acid starvation. It is therefore concluded that low levels of FLO11 transcripts are essential and sufficient for derepression of FLO11 expression and adhesive growth during amino acid starvation. A posttranscriptional control is assumed to be behind this phenomenon that permits the increased FLO11 expression from low FLO11 transcript abundances.
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PMID:Posttranscriptional regulation of FLO11 upon amino acid starvation in Saccharomyces cerevisiae. 1799 76

A gene encoding Trypanosoma brucei UDP-N-acetylglucosamine pyrophosphorylase was identified, and the recombinant protein was shown to have enzymatic activity. The parasite enzyme is unusual in having a strict substrate specificity for N-acetylglucosamine 1-phosphate and in being located inside a peroxisome-like microbody, the glycosome. A bloodstream form T. brucei conditional null mutant was constructed and shown to be unable to sustain growth in vitro or in vivo under nonpermissive conditions, demonstrating that there are no alternative metabolic or nutritional routes to UDP-N-acetylglucosamine and providing a genetic validation for the enzyme as a potential drug target. The conditional null mutant was also used to investigate the effects of N-acetylglucosamine starvation in the parasite. After 48 h under nonpermissive conditions, about 24 h before cell lysis, the status of parasite glycoprotein glycosylation was assessed. Under these conditions, UDP-N-acetylglucosamine levels were less than 5% of wild type. Lectin blotting and fluorescence microscopy with tomato lectin revealed that poly-N-acetyllactosamine structures were greatly reduced in the parasite. The principal parasite surface coat component, the variant surface glycoprotein, was also analyzed. Endoglycosidase digestions and mass spectrometry showed that, under UDP-N-acetylglucosamine starvation, the variant surface glycoprotein was specifically underglycosylated at its C-terminal Asn-428 N-glycosylation site. The significance of this finding, with respect to the hierarchy of site-specific N-glycosylation in T. brucei, is discussed.
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PMID:The synthesis of UDP-N-acetylglucosamine is essential for bloodstream form trypanosoma brucei in vitro and in vivo and UDP-N-acetylglucosamine starvation reveals a hierarchy in parasite protein glycosylation. 1838 Dec 90

Drug transport and disposition are influenced by a non-specific and reversible drug binding to plasma and tissues proteins. Albumin and al acid glycoprotein are the most important transport proteins of the blood. Albumin possesses specific sites for acidic and basic drug binding and can interact with them in the plasma since a third site is trapped only by digoxin. Diseases and stress conditions induce conformational changes either in plasma or in tissue proteins by the synthesis of endogenous substances which can strong interfere with the amount of the free pharmacological effective drug ratio. This may affect the binding of drugs in target molecules inducing significant pharmacokinetic alterations. Stress conditions are associated with FFA increase in serum playing an antagonistic role with other acidic molecules (e.g. ampicillin) to the same binding site. The bounded drug is displaced and freer ratio is available to interact with various organ receptors leading to pharmacological effect enhancement and therefore to side effects manifestation such as seizures. Furthermore conjunctive tissues diseases, ageing, prolonged bleeding, starvation or diseases affecting protein profile, characterized by reduced total plasma proteins, followed by albumin decrease and lessen binding sites lead to more free drug availability enhancing its pharmacological effect. Increased a1-acid glycoprotein the acute phase protein as by heart infraction or liver morbidities (e.g CCl4 intoxication) mainly occupied from basic substances, in the case of cationic drug treatment resulted to the enhancement of them and consequently to pronounced effectiveness. In addition, renal failure reduced free fractions of many acidic drugs. It may be concluded that by narrowed therapeutic index of a medicine, and when drug/drug or drug/disease interactions are anticipated, drug monitoring seems to be necessary for its dosage adjustment.
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PMID:The role of the protein-binding on the mode of drug action as well the interactions with other drugs. 1923 May 95


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