scholarly journals Folding initiation sites and protein folding.

1999 ◽  
Vol 46 (3) ◽  
pp. 487-508 ◽  
Author(s):  
M Dadlez
Keyword(s):  
Protein Folding ◽  
Protein Fragments ◽  
Denatured State ◽  
Local Structures ◽  
Rate Limiting Step ◽  
Structural Preferences ◽  
Low Levels ◽  
Rate Limiting ◽  
Transition State Barrier

The paper discusses the role of local structural preferences of protein segments in the folding of proteins. First a short overview of the local, secondary structures detected in peptides, protein fragments, denatured proteins and early folding intermediates is given. Next the discussion of their role in protein folding is presented based on recent literature and data obtained in our laboratory. In conclusion it is pointed out that, during folding, local structures populated at low levels in denatured state may facilitate the crossing of the folding transition state barrier, and consequently accelerate the rate limiting step in folding. However, the data show that this effect does not follow simple rules.

scholarly journals The metabolism of S-nitrosothiols in the trypanosomatids: the role of ovothiol A and trypanothione

2003 ◽  
Vol 371 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Ryan N. VOGT ◽  
Daniel J. STEENKAMP
Keyword(s):  
Reductase Activity ◽  
Order Rate Constant ◽  
Second Order ◽  
Formaldehyde Dehydrogenase ◽  
Thiyl Radicals ◽  
Order Rate ◽  
Rate Limiting Step ◽  
Low Levels ◽  
Rate Limiting

It has recently been established that nitrosoglutathione is the preferred substrate of the glutathione-dependent formaldehyde dehydrogenase from divergent organisms. Trypanosomatids produce not only glutathione, but also glutathionylspermidine, trypanothione and ovothiol A. The formaldehyde dehydrogenase activity of Crithidia fasciculata was independent of these thiols and extracts possessed very low levels of nitrosothiol reductase activity with glutathione or its spermidine conjugates as the thiol component. Although ovothiol A did not form a stable nitrosothiol, it decomposed the S-nitroso groups of nitrosoglutathione (GSNO) and dinitrotrypanothione [T(SNO)2] with second-order rate constants of 19.12M-1·s-1 and 8.67M-1·s-1 respectively. The reaction of T(SNO)2 with ovothiol A, however, accelerated to a rate similar to that seen with GSNO. Ovothiol A can act catalytically to decompose these nitrosothiols, although non-productive mechanisms exist. The catalytic phase of the reaction was dependent on the production of thiyl radicals, since it was abolished in the presence of 5,5-dimethyl-1-pyrroline-N-oxide and the formation of nitric oxide could be detected by means of the conversion of oxyhaemoglobin into methaemoglobin. The rate-limiting step in the catalytic process was the reduction of oxidized ovothiol species and, in this respect, T(SNO)2 is a more efficient substrate than GSNO. Trypanothione decomposed GSNO with a second-order rate constant of 0.786M-1·s-1 and the major nitrogenous end product changed from nitrite to ammonia as the ratio of thiol to nitrosothiol increased. The results indicate that ovothiol A acts in synergy with trypanothione in the decomposition of T(SNO)2.

Adenoviral expression of 15-lipoxygenase-1 in rabbit aortic endothelium: role in arachidonic acid-induced relaxation

2007 ◽  
Vol 292 (2) ◽  
pp. H1033-H1041 ◽  
Author(s):  
Nitin T. Aggarwal ◽  
Blythe B. Holmes ◽  
Lijie Cui ◽  
Helena Viita ◽  
Seppo Yla-Herttuala ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Arachidonic Acid ◽  
Rabbit Aorta ◽  
Epoxyeicosatrienoic Acid ◽  
Aortic Endothelial Cells ◽  
Aortic Endothelium ◽  
Rate Limiting Step ◽  
Immunohistochemical Studies ◽  
Rate Limiting

Endothelium-dependent vasorelaxation of the rabbit aorta is mediated by either nitric oxide (NO) or arachidonic acid (AA) metabolites from cyclooxygenase (COX) and 15-lipoxygenase (15-LO) pathways. 15-LO-1 metabolites of AA, 11,12,15-trihydroxyeicosatrienoic acid (THETA), and 15-hydroxy-11,12-epoxyeicosatrienoic acid (HEETA) cause concentration-dependent relaxation. We tested the hypothesis that in the 15-LO pathway of AA metabolism, 15-LO-1 is sufficient and is the rate-limiting step in inducing relaxations in rabbit aorta. Aorta and rabbit aortic endothelial cells were treated with adenoviruses containing human 15-LO-1 cDNA (Ad-15-LO-1) or β-galactosidase (Ad-β-Gal). Ad-15-LO-1-transduction increased the expression of a 75-kDa protein corresponding to 15-LO-1, detected by immunoblotting with an anti-human15-LO-1 antibody, and increased the production of HEETA and THETA from [14C]AA. Immunohistochemical studies on Ad-15-LO-1-transduced rabbit aorta showed the presence of 15-LO-1 in endothelial cells. Ad-15-LO-1-treated aortic rings showed enhanced relaxation to AA (max 31.7 ± 3.2%) compared with Ad-β-Gal-treated (max 12.7 ± 3.2%) or control nontreated rings (max 13.1 ± 1.6%) ( P < 0.01). The relaxations in Ad-15-LO-1-treated aorta were blocked by the 15-LO inhibitor cinnamyl-3,4-dihydroxy-a-cyanocinnamate. Overexpression of 15-LO-1 in the rabbit aortic endothelium is sufficient to increase the production of the vasodilatory HEETA and THETA and enhance the relaxations to AA. This confirms the role of HEETA and THETA as endothelium-derived relaxing factors.

Daily prolactin pulse inhibits the corpus luteum during lactational quiescence in the marsupial, Macropus eugenii

2013 ◽  
Vol 25 (2) ◽  
pp. 456 ◽  
Author(s):  
L. A. Hinds ◽  
C. H. Tyndale-Biscoe
Keyword(s):  
Corpus Luteum ◽  
Tammar Wallaby ◽  
Marked Contrast ◽  
Previous Conclusion ◽  
Macropus Eugenii ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Progesterone Synthesis ◽  
Rate Limiting

The corpus luteum (CL) of the tammar wallaby is inhibited by prolactin during lactation and seasonal quiescence. In seasonal quiescence a daily transient pulse of prolactin (PRL) of less than 2 h duration is sufficient to maintain inhibition. We investigated whether the same inhibition applies in lactation and, if so, how. Our results show that inhibition of the CL during lactation is maintained by a transient pulse of prolactin once a day. They also show that the minimum time without a PRL pulse for the CL to escape inhibition is more than 48 h and less than 72 h. Nevertheless, some animals had a longer refractory period than 72 h, which was reflected in a longer interval to the progesterone peak and birth. These results support the previous conclusion that PRL exercises its effect on a rate-limiting step in progesterone synthesis and secretion rate from the CL, which precedes any increase in its mass. Therefore, we conclude that the role of PRL is to act as a luteostatic agent, an effect that is in marked contrast to its luteotrophic effect in many eutherian species, including rodents.

scholarly journals Syntaxin-6 SNARE Involvement in Secretory and Endocytic Pathways of Cultured Pancreatic β-Cells

2004 ◽  
Vol 15 (4) ◽  
pp. 1690-1701 ◽  
Author(s):  
Regina Kuliawat ◽  
Elena Kalinina ◽  
Jason Bock ◽  
Lloyd Fricker ◽  
Timothy E. McGraw ◽  
...  
Keyword(s):  
Secretory Granules ◽  
Expression System ◽  
Secretory Cells ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Rate Limiting Step ◽  
Protein Receptor ◽  
Golgi Network ◽  
Rate Limiting

In pancreatic β-cells, the syntaxin 6 (Syn6) soluble N-ethylmaleimide-sensitive factor attachment protein receptor is distributed in the trans-Golgi network (TGN) (with spillover into immature secretory granules) and endosomes. A possible Syn6 requirement has been suggested in secretory granule biogenesis, but the role of Syn6 in live regulated secretory cells remains unexplored. We have created an ecdysone-inducible gene expression system in the INS-1 β-cell line and find that induced expression of a membrane-anchorless, cytosolic Syn6 (called Syn6t), but not full-length Syn6, causes a prominent defect in endosomal delivery to lysosomes, and the TGN, in these cells. The defect occurs downstream of the endosomal branchpoint involved in transferrin recycling, and upstream of the steady-state distribution of mannose 6-phosphate receptors. By contrast, neither acquisition of stimulus competence nor the ultimate size of β-granules is affected. Biosynthetic effects of dominant-interfering Syn6 seem limited to slowed intragranular processing to insulin (achieving normal levels within 2 h) and minor perturbation of sorting of newly synthesized lysosomal proenzymes. We conclude that expression of the Syn6t mutant slows a rate-limiting step in endosomal maturation but provides only modest and potentially indirect interference with regulated and constitutive secretory pathways, and in TGN sorting of lysosomal enzymes.

BACE1: a key regulator in Alzheimer’s disease progression and current development of its inhibitors

2021 ◽  
Vol 19 ◽  
Author(s):  
Smith Patel ◽  
Ankush Vardhaman Bansoad ◽  
Rakesh Singh ◽  
Gopal L. Khatik
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Status ◽  
Current Development ◽  
Quality Work ◽  
Rate Limiting Step ◽  
Disease Modifying Treatment ◽  
Rate Limiting

Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease where no specific disease-modifying treatment is currently available. β-secretase (BACE1) is considered the potential and rationale target because it is involved in the rate-limiting step, which produces toxic Aβ42 peptides leading to deposits in the form of amyloid plaques extracellularly leading to AD. Objective: The role and implications of BACE1 and its inhibitors in the management of AD are discussed. Methods: We have searched and collected the relevant quality work from PubMed using the following keywords “BACE1”, BACE2”, “inhibitors”, and “Alzheimer’s disease”. In addition, we included the work which discusses the role of BACE1 in AD and the recent work on its inhibitors. Results: In this review, we have discussed the importance of BACE1 in regulating AD progression and the current development of BACE1 inhibitors. However, the development of a BACE1 inhibitor is very challenging due to the large active site of BACE1. Nevertheless, some of the BACE1 inhibitors have managed to enter advanced phases of clinical trials, such as MK-8931 (Verubecestat), E2609 (Elenbecestat), AZD3293 (Lanabecestat), and JNJ-54861911 (Atabecestat). This review also sheds light on the prospect of BACE1 inhibitors as the most effective therapeutic approach in delaying or preventing AD progression. Conclusion: BACE1 is involved in the progression of AD. The current ongoing or failed clinical trials may help understand the role of BACE1 inhibition in regulating the Aβ load and cognitive status of AD patients.

scholarly journals Metabolic Engineering of Corynebacterium glutamicum for Trehalose Overproduction: Role of the TreYZ Trehalose Biosynthetic Pathway

2006 ◽  
Vol 72 (3) ◽  
pp. 1949-1955 ◽  
Author(s):  
Jorge Carpinelli ◽  
Reinhard Krämer ◽  
Eduardo Agosin
Keyword(s):  
Corynebacterium Glutamicum ◽  
Specific Productivity ◽  
Partial Recovery ◽  
Glycogen Accumulation ◽  
Production Methods ◽  
Homologous Overexpression ◽  
Rate Limiting Step ◽  
Potential Applications ◽  
Rate Limiting

ABSTRACT Trehalose has many potential applications in biotechnology and the food industry due to its protective effect against environmental stress. Our work explores microbiological production methods based on the capacity of Corynebacterium glutamicum to excrete trehalose. We address here raising trehalose productivity through homologous overexpression of maltooligosyltrehalose synthase and the maltooligosyltrehalose trehalohydrolase genes. In addition, heterologous expression of the UDP-glucose pyrophosphorylase gene from Escherichia coli improved the supply of glycogen. Gene expression effects were tested on enzymatic activities and intracellular glycogen content, as well as on accumulated and excreted trehalose. Overexpression of the treY gene and the treY/treZ synthetic operon significantly increased maltooligosyltrehalose synthase activity, the rate-limiting step, and improved the specific productivity and the final titer of trehalose. Furthermore, a strong decrease was noted in glycogen accumulation. Expression of galU/treY and galU/treYZ synthetic operons showed a partial recovery in the intracellular glycogen levels and a significant improvement in both intra- and extracellular trehalose content.

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