Nτ-methylhistidine – An index of the true rate of myofibrillar degradation? An appraisal

The use of N^τ-methylhistidine excretion as an index of myofibrillar protein breakdown is reviewed. It is suggested that several criteria should be considered before the technique can be considered valid and these include (i) there should be no reutilization of His (τMe) during protein synthesis, (ii) there should be little change in the His (τMe) content of the muscle during development, (iii) the metabolism, if any, of the His (τMe) should be minimal, (iv) the diet should contain no His (τMe), (v) there should be no other significant source of His (τMe) in the animal other than myofibrillar protein. Following consideration of these factors and of the data obtained using the technique, it is concluded that, with caution, it can be considered a valuable tool in the study of myofibrillar protein breakdown.     

Permanent direct His bundle pacing: initial report showing technical feasibility of an alternative pacing therapy

To prevent deterioration of left ventricular function during right ventricular apical pacing, permanent direct His bundle stimulation can be considered in selected patients with low left ventricular ejection fraction and a normal His-ventricle conduction time. We describe our first short-term experiences with permanent direct His bundle pacing in three patients. In two patients His bundle stimulation was still effective at six weeks'' follow-up. In one patient loss of capture was registered, after which conventional RV apical pacing was performed.     

Quantum chemical study of the "catalytic triad" of serine proteases

Using the semi-empirical MNDO/H method several systems simulating the reaction of tetrahedral intermediate formation in the active site of serine proteases have been studied. The role played by elements of the "catalytic triad" in increasing the reactivity of serine hydroxyl has been discussed. The formation of a strong hydrogen bond between His and Asp was shown to be important in lowering the activation energy in the reaction of Ser with substrate. The change in position of the proton located between Ser and His and between His and Asp was analysed. The influence of substrate distortion on the energy of intermediate formation has been considered.     

Anton van Leeuwenhoek (1632–1723) et la première description du spermatozoïde

Leeuwenhoek, father of light microscopy, is considered to be the founder of bacteriology and proto-zoology. His great merit in the field of andrology is to have discovered and studied the spermatozoon.     

Resolution after radiotherapy of severe pulmonary damage due to paraquat poisoning.

A 29 year old man was admitted 36 hours after ingesting about 5 g paraquat. His arterial oxygen pressure fell progressively to 3.4 kPa (34 mm Hg), and pulmonary damage induced by paraquat was diagnosed. His condition did not improve after treatment with prednisolone and cyclophosphamide, but after irradiation both lungs cleared and arterial oxygen pressure started to improve. Irradiation of the lungs should be considered in patients who, after surviving the acute phase of poisoning with paraquat, show progressive deterioration of respiratory function.     

His92 and His110 selectively affect different heme centers of adrenal cytochrome b(561)

Adrenal cytochrome b(561) (cyt b(561)), a transmembrane protein that shuttles reducing equivalents derived from ascorbate, has two heme centers with distinct spectroscopic signals and reactivity towards ascorbate. The His54/His122 and His88/His161 pairs furnish axial ligands for the hemes, but additional amino acid residues contributing to the heme centers have not been identified. A computational model of human cyt b(561) (Bashtovyy, D., Berczi, A., Asard, H., and Pali, T. (2003) Protoplasma 221, 31-40) predicts that His92 is near the His88/His161 heme and that His110 abuts the His54/His122 heme. We tested these predictions by analyzing the effects of mutations at His92 or His110 on the spectroscopic and functional properties. Wild type cytochrome and mutants with substitutions in other histidine residues or in Asn78 were used for comparison. The largest lineshape changes in the optical absorbance spectrum of the high-potential (b(H)) peak were seen with mutation of His92; the largest changes in the low-potential (b(L)) peak lineshape were observed with mutation of His110. In the EPR spectra, mutation of His92 shifted the position of the g=3.1 signal (b(H)) but not the g=3.7 signal (b(L)). In reductive titrations with ascorbate, mutations in His92 produced the largest increase in the midpoint for the b(H) transition; mutations in His110 produced the largest decreases in DeltaA(561) for the b(L) transition. These results indicate that His92 can be considered part of the b(H) heme center, and His110 part of the b(L) heme center, in adrenal cyt b(561).     

A drought-stress-inducible histone gene in Arabidopsis thaliana is a member of a distinct class of plant linker histone variants

We have isolated and characterized a gene, His1-3, encoding a structurally divergent linker histone in Arabidopsis thaliana. Southern and northern hybridization data indicate that A. thaliana expresses three single-copy linker histone genes, each encoding a structurally distinct variant. H1-3 is a considerably smaller protein (167 amino acids with a mass of 19.0 kDa) than any other described linker histone from higher eukaryotes. We examined the expression of His1-3 at the RNA and protein levels and found that it is induced specifically by water stress. In contrast, expression of His1-1, His1-2 and His4 appear unaffected by water stress. Furthermore, the primary structure of the protein possesses distinct characteristics that are shared with another drought-inducible linker histone, H1-D, isolated from Lycopersicon pennellii. Based on structural characteristics of the deduced protein and its inducible expression, we hypothesize that H1-3 and H1-D are linker histone variants that have specialized roles in the structure and function of plant chromatin and therefore they can be considered to be members of a unique subclass of plant histones. Immunoblotting with an antibody produced against a short polypeptide in the conserved domain of this subtype indicates that similar proteins may exist in other plants.     

200 years since the birth of Charles Darwin and 150 years since the publication of <Emphasis Type="Italic">On the Origin of Species</Emphasis>

In 2009 we celebrate the 200th anniversary of the birth of Ch. R. Darwin, an English naturalist. His life and career as an outstanding biologist and famous geologist, are considered. His ideas and influence on the scientific community are discussed.     

Aristote (384–322): biologiste de la réproduction avant la lettre

Born in Chalcidice, Greece, in 384 BC and died in Chalcis in 322 BC, Aristotle, an Athenian philosopher, made considerable contributions to the fields of anatomy, zoology and biology. His research and texts on reproduction biology made a major contribution to the development of this discipline and Aristotle is rightly considered to be a pioneer in this field.     

His92 and His110 selectively affect different heme centers of adrenal cytochrome b561

Adrenal cytochrome b₅₆₁ (cyt b₅₆₁), a transmembrane protein that shuttles reducing equivalents derived from ascorbate, has two heme centers with distinct spectroscopic signals and reactivity towards ascorbate. The His54/His122 and His88/His161 pairs furnish axial ligands for the hemes, but additional amino acid residues contributing to the heme centers have not been identified. A computational model of human cyt b₅₆₁ (Bashtovyy, D., Berczi, A., Asard, H., and Pali, T. (2003) Protoplasma 221, 31-40) predicts that His92 is near the His88/His161 heme and that His110 abuts the His54/His122 heme. We tested these predictions by analyzing the effects of mutations at His92 or His110 on the spectroscopic and functional properties. Wild type cytochrome and mutants with substitutions in other histidine residues or in Asn78 were used for comparison. The largest lineshape changes in the optical absorbance spectrum of the high-potential (b_H) peak were seen with mutation of His92; the largest changes in the low-potential (b_L) peak lineshape were observed with mutation of His110. In the EPR spectra, mutation of His92 shifted the position of the g = 3.1 signal (b_H) but not the g = 3.7 signal (b_L). In reductive titrations with ascorbate, mutations in His92 produced the largest increase in the midpoint for the b_H transition; mutations in His110 produced the largest decreases in ΔA₅₆₁ for the b_L transition. These results indicate that His92 can be considered part of the b_H heme center, and His110 part of the b_L heme center, in adrenal cyt b₅₆₁.     

The clinical relevance and prognostic significance of microsomal epoxide hydrolase gene polymorphisms and their susceptibility to acquired aplastic anemia: an Egyptian study

Background: Microsomal epoxide hydrolase enzyme (mEPHX) is involved in xenobiotics detoxification. Two variants of mEPHX, Tyr113His and His139Arg, have been described. Both may lead to acquired aplastic anemia (AA).

Objectives: Assessing mEPHX genetic polymorphisms and detecting their impact on susceptibility and prognosis in Egyptian AA patients.

Participants and methods: mEPHX 113 and 139 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 100 patients with AA and 100 control subjects.

Results: Both mEPHX Tyr113His and His139Arg gene polymorphisms were associated with increased risk of developing AA, and have a significant impact of bad prognosis (p value?<?0.01).

Conclusions: These mEPHX gene polymorphisms can be considered as risk factors and predictive molecular markers for prognosis in AA patients.     

Aromatic side-chain interactions in proteins. Near- and far-sequence His–X pairs

Several studies have analysed aromatic interactions, involving mostly phenylalanine, tyrosine and tryptophan. Only a few studies have considered histidine as an interacting aromatic residue. An extensive analysis of aromatic His–X interactions is performed here on a data set of 593 PDB structures: 68% of the histidine are involved in aromatic pairs and 1271 non-redundant His–X pairs were analysed. Thirty percent of these pairs involve an aromatic partner less than 6 apart in the sequence. These near-sequence pairs correspond to conformations which stabilise secondary structures, mainly α-helices when the residues are 4 apart and β-strands when they are 2 apart in the sequence. The partners of the other His–X pairs (887, 70%) are more than 5 apart in the sequence. Of these far-sequence pairs, 35% bridge beta strands and only 9% helices. The near-sequence pairs are sterically constrained as supported by conformer distribution. The X partners of far-sequence His–X pairs are mainly “above” the histidine ring with tilted and normal rings, corresponding to a “T shape; face to edge” orientation. Phenylalanine, the only aromatic residue with no heteroatom, is a disfavoured partner, whereas histidine is the preferred one. Heteroatom–heteroatom interactions are favoured in near-sequence as well as in far-sequence His–His, His–Trp and His–Tyr pairs.     

A study of the interaction between tRNASer and seryl-tRNA synthetase from bovine liver

Study by chemical modification of Ser, Arg, His residues and sulfhydryl groups on bovine seryl-tRNA synthetase showed that Ser residues appeared to be unnecessary for the recognition mechanism, but Arg and His residues were essential. It was considered that different sulfhydryl groups related with each recognition of tRNA and ATP. Poly-arginine inhibited the interaction between serine tRNA and SerRS. The CD spectra of a mixture of serine tRNA and poly-arginine indicated that higher-order structure of tRNA changed. Furthermore, the Km and Vmax values of bovine serine isoacceptor, yeast serine tRNA and E. coli serine tRNA for bovine SerRS examined and it was discussed the differences of those base sequences.     

Minimal Zn(2+) binding site of amyloid-β

Zinc-induced aggregation of amyloid-β peptide (Aβ) is a hallmark molecular feature of Alzheimer's disease. Here we provide direct thermodynamic evidence that elucidates the role of the Aβ region 6-14 as the minimal Zn(2+) binding site wherein the ion is coordinated by His(6), Glu(11), His(13), and His(14). With the help of isothermal titration calorimetry and quantum mechanics/molecular mechanics simulations, the region 11-14 was determined as the primary zinc recognition site and considered an important drug-target candidate to prevent Zn(2+)-induced aggregation of Aβ.     

Mechanical insights of oxythiamine compound as potent inhibitor for human transketolase-like protein 1 (TKTL1 protein)

Transketolase is a connecting link between glycolytic and pentose phosphate pathway, which is considered as the rate-limiting step due to synthesis of large number of ATP molecule and it can be proposed as a plausible target facilitating the growth of cancerous cells suggesting its potential role in cancer. Oxythiamine, an antimetabolite has been proved to be an efficient anticancerous compound in vitro, but its structural elucidation of the inhibitory mechanism has not yet been done against the human transketolase-like 1 protein (TKTL1). The three-dimensional (3D) structure of TKTL1 protein was modeled and subjected for refinement, stability and validation. Based on the reported homologs of transketolase (TKT), the active site residues His46, Ser49, Ser52, Ser53, Ile56, Leu82, Lys84, Leu123, Ser125, Glu128, Asp154, His160, Thr216 and Lys218 were identified and considered for molecular-modeling studies. Docking studies reveal the H-bond interactions with residues Ser49 and Lys218 that could play a major role in the activity of TKTL1. Molecular dynamics (MD) simulation study was performed to reveal the comparative stability of both native and complex forms of TKTL1. MD trajectory at 30?ns, confirm the role of active site residues Ser49, Lys84, Glu128, His160 and Lys218 in suppressing the activity of TKTL1. Glu128 is observed to be the most important residue for deprotonation state of the aminopyrimidine moiety and preferred to be the site of inhibitory action. Thus, the proposed mechanism of inhibition through in silico studies would pave the way for structure-oriented drug designing against cancer.     

Hydration of CO2 by carbonic anhydrase: intramolecular proton transfer between Zn2+-bound H2O and histidine 64 in human carbonic anhydrase II

The energy barrier for the intramolecular proton transfer between zinc-bound water and His 64 in the active site of human carbonic anhydrase II (HCA II) has been studied at the partial retention of diatomic differential overlap (PRDDO) level. The most important stabilizing factor for the intramolecular proton transfer is the zinc ion, which lowers the pKa of zinc-bound water and electrostatically repels the proton. The energy barrier of 127.5 kcal/mol for proton transfer between a water dimer is completely removed in the presence of the zinc ion. The zinc ligands, which donate electrons to the zinc ion, raise the barrier slightly to 34 kcal/mol for a 4-coordinated zinc complex including three imidazole ligands from His 94, His 96, and His 119 and to 54 kcal/mol for the 5-coordinated zinc complex including the fifth water ligand. A few model calculations indicate that these energy barriers are expected to be reduced to within experimental range (approximately 10 kcal/mol) when large basis set, correlation energies, and molecular dynamics are considered. The proton-transfer group, which functions as proton receiver in the intramolecular proton transfer, helps to attract the proton; and the partially ordered active site water molecules are important for proton relay function.     

Paul Ehrlich--in search of the magic bullet

In 2004, we celebrate the 150th anniversary of the birth of Paul Ehrlich, considered the founder of immunology. His life and work can be divided into three creative periods: first, he developed histological staining, then he accomplished his ground-breaking work on immunology, and eventually invented chemotherapy. Paul Ehrlich can be perceived as a man whose success was not the consequence of a will to power, but of his substantial interest in science.     

Structural changes of region 1-16 of the Alzheimer disease amyloid beta-peptide upon zinc binding and in vitro aging

Amyloid deposits within the cerebral tissue constitute a characteristic lesion associated with Alzheimer disease. They mainly consist of the amyloid peptide Abeta and display an abnormal content in Zn(2+) ions, together with many truncated, isomerized, and racemized forms of Abeta. The region 1-16 of Abeta can be considered the minimal zinc-binding domain and contains two aspartates subject to protein aging. The influence of zinc binding and protein aging related modifications on the conformation of this region of Abeta is of importance given the potentiality of this domain to constitute a therapeutic target, especially for immunization approaches. In this study, we determined from NMR data the solution structure of the Abeta-(1-16)-Zn(2+) complex in aqueous solution at pH 6.5. The residues His(6), His(13), and His(14) and the Glu(11) carboxylate were identified as ligands that tetrahedrally coordinate the Zn(II) cation. In vitro aging experiments on Abeta-(1-16) led to the formation of truncated and isomerized species. The major isomer generated, Abeta-(1-16)-l-iso-Asp(7), displayed a local conformational change in the His(6)-Ser(8) region but kept a zinc binding propensity via a coordination mode involving l-iso-Asp(7). These results are discussed here with regard to Abeta fibrillogenesis and the potentiality of the region 1-16 of Abeta to be used as a therapeutic target.