Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0271742 (AAA)
 3,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the characteristics of ethylene biosynthesis associated with ripening in banana (Musa sp. [AAA group, Cavendish subgroup] cv Grand Nain) fruit. MA-ACS1 encoding 1-aminocyclopropane-1-carboxylic acid (ACC) synthase in banana fruit was the gene related to the ripening process and was inducible by exogenous ethylene. At the onset of the climacteric period in naturally ripened fruit, ethylene production increased greatly, with a sharp peak concomitant with an increase in the accumulation of MA-ACS1 mRNA, and then decreased rapidly. At the onset of ripening, the in vivo ACC oxidase activity was enhanced greatly, followed by an immediate and rapid decrease. Expression of the MA-ACO1 gene encoding banana ACC oxidase was detectable at the preclimacteric stage, increased when ripening commenced, and then remained high throughout the later ripening stage despite of a rapid reduction in the ACC oxidase activity. This discrepancy between enzyme activity and gene expression of ACC oxidase could be, at least in part, due to reduced contents of ascorbate and iron, cofactors for the enzyme, during ripening. Addition of these cofactors to the incubation medium greatly stimulated the in vivo ACC oxidase activity during late ripening stages. The results suggest that ethylene production in banana fruit is regulated by transcription of MA-ACS1 until climacteric rise and by reduction of ACC oxidase activity possibly through limited in situ availability of its cofactors once ripening has commenced, which in turn characterizes the sharp peak of ethylene production.
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PMID:Characterization of ethylene biosynthesis associated with ripening in banana fruit. 1059 12

In mammalian cells, mitochondria provide energy from aerobic metabolism. They play an important regulatory role in apoptosis, produce and detoxify free radicals, and serve as a cellular calcium buffer. Neurodegenerative disorders involving mitochondria can be divided into those caused by oxidative phosphorylation (OXPHOS) abnormalities either due to mitochondrial DNA (mtDNA) abnormalities, e.g., chronic external ophthalmoplegia, or due to nuclear mutations of OXPHOS proteins, e.g., complex I and II associated with Leigh syndrome. There are diseases caused by nuclear genes encoding non-OXPHOS mitochondrial proteins, such as frataxin in Friedreich ataxia (which is likely to play an important role in mitochondrial-cytosolic iron cycling), paraplegin (possibly a mitochondrial ATP-dependent zinc metalloprotease of the AAA-ATPases in hereditary spastic paraparesis), and possibly Wilson disease protein (an abnormal copper transporting ATP-dependent P-type ATPase associated with Wilson disease). Huntingon disease is an example of diseases with OXPHOS defects associated with mutations of nuclear genes encoding non-mitochondrial proteins such as huntingtin. There are also disorders with evidence of mitochondrial involvement that cannot as yet be assigned. These include Parkinson disease (where a complex I defect is described and free radicals are generated from dopamine metabolism), amyotrophic lateral sclerosis, and Alzheimer disease, where there is evidence to suggest mitochondrial involvement perhaps secondary to other abnormalities.
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PMID:Mitochondria and degenerative disorders. 1157 22

We previously reported a patient with hereditary hypotransferrinemia who suffered from severe anemia and growth retardation and was diagnosed on the basis of an extremely low level of serum transferrin (TF). By an isoelectric focusing analysis, we found that the patient and his father shared a variant TF protein with an abnormal isoelectric point. The study suggested that the patient was a compound heterozygote with a variant allele, encoding the mutant TF, of paternal origin and a null allele of maternal origin. In the present study, we investigated the TF gene of the patient and his family. We showed that the patient and his father shared a variant TF gene bearing a GAA to AAA transition at codon 394. This nucleotide substitution causes a nonconservative amino acid change from glutamate to lysine in amino acid residue 375 of the TF protein. This single amino acid mutation is predicted to cause a conformational change in the coiled region of the carboxyl-terminal iron-binding lobe. As for the maternal null allele, no mutation was found in either the coding region or the exon-intron boundaries, suggesting an abnormality in the transcription or stability of mRNA of maternal allele origin.
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PMID:Molecular analysis of the transferrin gene in a patient with hereditary hypotransferrinemia. 1211 69

We previously identified a gene, slr0374, in the unicellular cyanobacterium, Synechocystis sp. strain PCC 6803, that was highly expressed under iron-deficient conditions [J. Bacteriol. 182 (2000) 3536]. The gene product contains an AAA domain, a putative leucine zipper and a phosphorylation site and is part of an operon (with slr0373 and slr0376) that is responsive to various environmental stresses. Primer extension mapping and transcript analysis in insertion mutants showed that all transcripts from this operon originated upstream of slr0373 at four contiguous transcription start sites before being processed into individual transcripts. Both primary and processed transcripts were quite stable. The start sites were sensitive to changes in sulfur, light and redox agent, as well as iron. The structural and regulatory elements of this operon were highly conserved in phycobilisome-containing cyanobacteria that have been sequenced to date. Slr0374 and Slr0376 show homology with Ycf46 and Ycf35, respectively.
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PMID:Characterization of a stress-responsive operon in the cyanobacterium Synechocystis sp. strain PCC 6803. 1238 81

We investigated two unrelated children with an isolated defect of mitochondrial complex III activity. The clinical picture was characterized by a progressive encephalopathy featuring early-onset developmental delay, spasticity, seizures, lactic acidosis, brain atrophy and MRI signal changes in the basal ganglia. Both children were compound heterozygotes for novel mutations in the human bc1 synthesis like (BCS1L) gene, which encodes an AAA mitochondrial protein putatively involved in both iron homeostasis and complex III assembly. The pathogenic role of the mutations was confirmed by complementation assays, using a DeltaBcs1 strain of Saccharomyces cerevisiae. By investigating complex III assembly and the structural features of the BCS1L gene product in skeletal muscle, cultured fibroblasts and lymphoblastoid cell lines from our patients, we have demonstrated, for the first time in a mammalian system, that a major function of BCS1L is to promote the maturation of complex III and, more specifically, the incorporation of the Rieske iron-sulfur protein into the nascent complex. Defective BCS1L leads to the formation of a catalytically inactive, structurally unstable complex III. We have also shown that BCS1L is contained within a high-molecular-weight supramolecular complex which is clearly distinct from complex III intermediates.
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PMID:Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. 1740 14

OPA1, an intra-mitochondrial dynamin GTPase, is a key actor of outer and inner mitochondrial membrane dynamic. OPA1 amino-terminal cleavage by PARL and m-AAA proteases was recently proposed to participate to the mitochondrial network dynamic in a DeltaPsi(m)-dependent way, and to apoptosis. Here, by an in vitro approach combining the use of purified mitochondrial fractions and mitochondrial targeting drugs, we intended to identify the central stimulus responsible for OPA1 cleavage. We confirm that apoptosis induction and PTPore opening, as well as DeltaPsi(m) dissipation induce OPA1 cleavage. Nevertheless, our experiments evidenced that decreased mitochondrial ATP levels, either generated by apoptosis induction, DeltaPsi(m) dissipation or inhibition of ATP synthase, is the common and crucial stimulus that controls OPA1 processing. In addition, we report that ectopic iron addition activates OPA1 cleavage, whereas zinc inhibits this process. These results suggest that the ATP-dependent OPA1 processing plays a central role in correlating the energetic metabolism to mitochondrial dynamic and might be involved in the pathophysiology of diseases associated to excess of iron or depletion of zinc and ATP.
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PMID:OPA1 cleavage depends on decreased mitochondrial ATP level and bivalent metals. 1782 66

To date, direct analysis of mitochondrial proteomes has largely been limited to animals, fungi and plants. To broaden our knowledge of mitochondrial structure and function, and to provide additional insight into the evolution of this key eukaryotic organelle, we have undertaken the first comprehensive analysis of the mitochondrial proteome of a protist. Highly purified mitochondria from Tetrahymena thermophila, a ciliated protozoon, were digested exhaustively with trypsin and the resulting peptides subjected to tandem liquid chromatography-tandem mass spectrometry (LC/LC-MS/MS). In this way, we directly identified a total of 573 mitochondrial proteins, 545 of which are encoded by the nuclear genome and 28 by the mitochondrial genome. The latter number includes a novel, 44 residue protein (which we designate Ymf78) that had not been recognized during annotation of the T. thermophila mtDNA sequence. The corresponding gene, ymf78, is highly conserved in genomic position, size and sequence within the genus Tetrahymena. Our analysis has provided broad coverage of both membrane-bound and soluble proteins from the various submitochondrial compartments, with prominent representatives including components of the tricarboxylic acid cycle, Complexes I-IV of the electron transport chain and Complex V (ATP synthase), the mitochondrial transcription and translation machinery, the TOM and TIM protein translocases, various mitochondrial transporters, chaperonins (Cpn60, Hsp70, Hsp90), at least four FtsH family ATP-dependent metalloproteases implicated in m-AAA and i-AAA protease function, and enzymes involved in lipid, amino acid and coenzyme metabolism, as well as iron-sulfur cluster formation. Unexpectedly, six of the ten enzymes of glycolysis were found by MS analysis of purified T. thermophila mitochondria, whereas no hits were seen to any cytosolic ribosomal proteins. At least one of the glycolytic proteins, enolase, has an evident N-terminal extension that exhibits characteristics of a typical mitochondrial targeting peptide. As in other organisms, phylogenetic analysis of functionally annotated mitochondrial proteins demonstrates that <20% can be traced confidently to the alpha-proteobacterial lineage of Bacteria, emphasizing the chimeric evolutionary nature of the mitochondrial proteome. Notably, about 45% of the proteins identified in our analysis have no known function, and most of these do not have obvious homologs outside of the ciliate lineage. About two-thirds of these ORFan proteins have putative homologs in another ciliate, Paramecium tetraurelia, whereas the remainder appear to be Tetrahymena-specific. These results emphasize the power and importance of direct MS-based analysis of mitochondria in revealing novel mitochondrial proteins in different eukaryotic lineages. Our observations reinforce an emerging view of the mitochondrion as an evolutionarily flexible organelle, with novel proteins (and presumably functions) being added in a lineage-specific fashion to an ancient, highly conserved functional core, much of which was contributed by the presumptive alpha-proteobacterial symbiont from which the mitochondrial genome was derived.
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PMID:Exploring the mitochondrial proteome of the ciliate protozoon Tetrahymena thermophila: direct analysis by tandem mass spectrometry. 1795 97

Salicylic acid (SA) is a critical mediator of plant innate immunity. It plays an important role in limiting the growth and reproduction of the virulent powdery mildew (PM) Golovinomyces orontii on Arabidopsis (Arabidopsis thaliana). To investigate this later phase of the PM interaction and the role played by SA, we performed replicated global expression profiling for wild-type and SA biosynthetic mutant isochorismate synthase1 (ics1) Arabidopsis from 0 to 7 d after infection. We found that ICS1-impacted genes constitute 3.8% of profiled genes, with known molecular markers of Arabidopsis defense ranked very highly by the multivariate empirical Bayes statistic (T(2) statistic). Functional analyses of T(2)-selected genes identified statistically significant PM-impacted processes, including photosynthesis, cell wall modification, and alkaloid metabolism, that are ICS1 independent. ICS1-impacted processes include redox, vacuolar transport/secretion, and signaling. Our data also support a role for ICS1 (SA) in iron and calcium homeostasis and identify components of SA cross talk with other phytohormones. Through our analysis, 39 novel PM-impacted transcriptional regulators were identified. Insertion mutants in one of these regulators, PUX2 (for plant ubiquitin regulatory X domain-containing protein 2), results in significantly reduced reproduction of the PM in a cell death-independent manner. Although little is known about PUX2, PUX1 acts as a negative regulator of Arabidopsis CDC48, an essential AAA-ATPase chaperone that mediates diverse cellular activities, including homotypic fusion of endoplasmic reticulum and Golgi membranes, endoplasmic reticulum-associated protein degradation, cell cycle progression, and apoptosis. Future work will elucidate the functional role of the novel regulator PUX2 in PM resistance.
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PMID:Temporal global expression data reveal known and novel salicylate-impacted processes and regulators mediating powdery mildew growth and reproduction on Arabidopsis. 1917 22

The mitochondrial protein Bcs1p is conserved from Saccharomyces cerevisiae to humans and its C-terminal region exhibits an AAA (ATPases associated with diverse cellular activities) domain. The absence of the yeast Bcs1p leads to an assembly defect of the iron-sulfur protein (ISP) subunit within the mitochondrial respiratory complex III, whereas human point mutations located all along the protein cause various pathologies. We have performed a structure-function analysis of the yeast Bcs1p by randomly generating a collection of respiratory-deficient point mutants. We showed that most mutations are in the C-terminal region of Bcs1p and have localized them on a theoretical three-dimensional model based on the structure of several AAA proteins. The mutations can be grouped into classes according to their respiratory competence and their location on the three-dimensional model. We have further characterized five mutants, each substituting an amino acid conserved in yeast and mammalian Bcs1 proteins but not in other AAA proteins. The effects on respiratory complex assembly and Bcs1p accumulation were analyzed. Intragenic and extragenic compensatory mutations able to restore complex III assembly to the mutants affecting the AAA domain were isolated. Our results bring new insights into the role of specific residues in critical regions that are also conserved in the human Bcs1p. We show that (1) residues located at the junction between the Bcs1p-specific and the AAA domains are important for the activity and stability of the protein and (2) the residue F342 is important for interactions with other partners or substrate proteins.
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PMID:Functional analysis of yeast bcs1 mutants highlights the role of Bcs1p-specific amino acids in the AAA domain. 1928 91

Dominant selectable markers are beneficial for transformation of many fungi, particularly those model species where repeated transformations may be required. A carboxin resistance allele of the Coprinopsis cinerea sdi1 gene, encoding the iron-sulphur protein subunit of succinate dehydrogenase, was developed by introducing a suitable point mutation in the histidine block responsible for binding of the associated iron ion. This modified gene was used successfully to confer carboxin resistance upon transformation of C. cinerea protoplasts. Plasmids previously used to establish hygromycin transformation systems of several basidiomycete species, such as pAN7-1 and phph004, failed to give rise to hygromycin-resistant transformants of C. cinerea, whilst pPHT1 was successful. Sequencing of these constructs showed that the hygromycin resistance gene in pAN7-1 and phph004 had been modified removing the codons encoding two lysine residues following the N-terminal methionine. Replacement of the deleted 6 bp (AAA AAG) in the truncated hph gene led to generation of hygromycin-resistant transformants indicating the importance of these two codons for expression in C. cinerea. Phleomycin-resistant (ble) transformants were also obtained, but only with the intron-containing construct pblei004, showing that an intron is necessary to obtain phleomycin-resistant C. cinerea. This contrasts with hygromycin-resistance, where introns are not required for expression, emphasising the variability in importance of these elements.
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PMID:Investigating dominant selection markers for Coprinopsis cinerea: a carboxin resistance system and re-evaluation of hygromycin and phleomycin resistance vectors. 1963 58


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