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PubMed1998

Catastrophic progression of the disassembly of a modular acetabular component.

Disassembly of a metal-backed modular acetabular component used for total hip arthroplasty is becoming more common. If the acetabular disassembly is detected early, the revision procedures are relatively simple. In the case of long-term sustained disassembly, however, there are more complicated problems, and more difficult revision procedures are needed. We report a case of long-term sustained disassembly of a modular acetabular component in order to alert orthopaedic surgeons of the catastrophic progression to more severe complications, such as the loosening of the metal-acetabular component and severe acetabular osteolysis.

Acetabulum↗

PubMed1999

Temporal changes of periprosthetic bone density in patients with a modular noncemented femoral prosthesis.

Bone mineral density changes surrounding a porous-coated proximal modular sleeved hip prosthesis were determined as a function of time over a 24-month period. The periprosthetic bone regions were defined by the 7 Gruen zones. Measurements were obtained with a dual-energy x-ray densitometer using a dedicated software program. Inclusion criteria required that the patients had primary implants, were asymptomatic with Harris hip scores of > or =95 for the duration of the study, and showed no radiographic evidence of loosening. The protocol specified that bone measurements be obtained within 1 week after surgery as a baseline reference and at 3, 6, 9, 12, 18, and 24 months thereafter. A total of 111 consecutive patients were enrolled in this ongoing prospective study, of whom 52 had 4 or more measurements after the initial baseline determination for statistical analysis. At 3 months, all zones showed a significant decrease in bone mineral density relative to the baseline measurements, and their mean loss ranged from 6.5% to 11.2%. By 24 months, mineral losses relative to baseline varied from 0 to 11% for Gruen zones 1 to 6. Relative to the 3-month levels, there was no significant change in zones 1, 4, and 6; a significant improvement in zones 3 and 5; and a small but significant loss in zone 2 at 24 months. Gruen zone 7, the medial femoral neck cortex, differed in that it was the site of greatest bone mineral loss, attaining a mean of 20.2% at 24 months. It was found that the amount of periprosthetic mineral loss at 12 months was independent of the initial baseline reference bone mineral levels. Results of this study show the normal temporal bone mineral changes surrounding a proximally modular porouscoated femoral implant. The pattern of change demonstrated may be peculiar to the prosthesis used in this study because it might differ in implants of different design and material composition.

Absorptiometry, Photon↗

PubMed2000

Modular neural networks for non-linearity recovering by the Haar approximation.

The paper deals with the design of a composite neural system for recovering non-linear characteristics from random input-output measurement data. It is assumed that non-linearity output measurements are corrupted by an additive zero-mean white random noise and that the input excitation is an i.i.d. random sequence with an arbitrary (and unknown) probability density function. A class of modular networks is developed. The class is based on the Haar approximation of functions with piecewise constant functions on a refinable grid and consists of the networks composed of perceptron-like modules connected in parallel. The networks provide a local mean value estimators of functions. The relationship between complexity and accuracy of modular networks is analysed. It is shown that under mild conditions on the non-linearities and input probability density functions the networks yield pointwise consistent estimates of non-linear characteristics, provided that complexity of the networks grows appropriately with the number of training data. Efficiency of the networks is examined and the asymptotic rate of convergence of the network estimates is established. Specifically, local ability of the networks to recover non-linear characteristics in dependence on local smoothness of the underlying non-linear function and the input probability density is discussed. Optimum complexity selection rules, guaranteeing the best performance of the networks, are given. Illustrative simulation examples are provided.

Computer Simulation↗

PubMed2000

Introduction and evaluation of a modular seminar system in gross anatomy teaching at the Hannover Medical School.

We present a new modular seminar system which has been introduced into the gross anatomy teaching at the Hannover Medical School. It consists of seven modules with a clinical emphasis. The new modular seminar system was evaluated by an anonymous questionnaire. The results showed that the seminar system as a whole, and the different modules with one exception were highly appreciated by the students. The evaluation also revealed that the main reason for the success of a module is the manner of the teaching and learning rather than the clinical relevance. Taking into account the results of this evaluation we describe the appropriate style of teaching for use in a seminar. The success of this new approach to small group instruction in Germany should encourage other teachers of anatomy and other undergraduate subjects to consider new methods of teaching.

Anatomy↗

PubMed1998

The modular structure of actin-regulatory proteins.

Filamentous actin structures possess unique biophysical and biochemical properties and are required for cell locomotion, cell division, compartmentalization and morphological processes. The site-specific assembly and disassembly of these structures are directed by actin-regulatory proteins. This article reviews how structural studies are now defining the atomic details of small modular domains present in actin-regulatory proteins responsible for crosslinking, severing and capping of actin filaments, as well as for localization of actin filament assembly. These studies have identified three modular strategies for the design of proteins that regulate the actin cytoskeleton.

Actins↗

PubMed2003

The structure of docking domains in modular polyketide synthases.

Polyketides from actinomycete bacteria provide the basis for many valuable medicines, so engineering genes for their biosynthesis to produce variant molecules holds promise for drug discovery. The modular polyketide synthases are particularly amenable to this approach, because each cycle of chain extension is catalyzed by a different module of enzymes, and the modules are arranged within giant multienzyme subunits in the order in which they act. Protein-protein interactions between terminal docking domains of successive multienzymes promote their correct positioning within the assembly line, but because the overall complex is not stable in vitro, the key interactions have not been identified. We present here the NMR solution structure of a 120 residue polypeptide representing a typical pair of such domains, fused at their respective C and N termini: it adopts a stable dimeric structure which reveals the detailed role of these (predominantly helical) domains in docking and dimerization by modular polyketide synthases.

Amino Acid Sequence↗

PubMed1996

A hybrid modular polyketide synthase obtained by domain swapping.

BACKGROUND: Modular polyketide synthases govern the synthesis of a number of medically important antibiotics, and there is therefore great interest in understanding how genetic manipulation may be used to produce hybrid synthases that might synthesize novel polyketides. In particular, we aimed to show whether an individual domain can be replaced by a comparable domain from a different polyketide synthase to form a functional hybrid enzyme. To simplify the analysis, we have used our previously-developed model system DEBS1-TE, consisting of the first two chain-extension modules of the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea. RESULTS: We show here that replacing the entire acyltransferase (AT) domain from module 1 of DEBS1-TE by the AT domain from module 2 of the rapamycin-producing polyketide synthase leads, as predicted, to the synthesis of two novel triketide lactones in good yield, in place of the two lactones produced by DEBS1-TE. Both of the novel products specifically lack a methyl group at C-4 of the lactone ring. CONCLUSIONS: Although the AT domain is a core structural domain of a modular polyketide synthase, it has been swapped to generate a truly hybrid multienzyme with a rationally altered specificity of chain extension. Identical manipulations carried out on known polyketide antibiotics might therefore generate families of potentially useful analogues that are inaccessible by chemical synthesis. These results also encourage the belief that other domains may be similarly swapped.

Amino Acid Sequence↗

PubMed1997

The bacitracin biosynthesis operon of Bacillus licheniformis ATCC 10716: molecular characterization of three multi-modular peptide synthetases.

BACKGROUND: The branched cyclic dodecylpeptide antibiotic bacitracin, produced by special strains of Bacillus, is synthesized nonribosomally by a large multienzyme complex composed of the three bacitracin synthetases BA1, BA2 and BA3. These enzymes activate and incorporate the constituent amino acids of bacitracin by a thiotemplate mechanism in a pathway driven by a protein template. The biochemical features of these enzymes have been studied intensively but little is known about the molecular organization of their genes. RESULTS: The entire bacitracin synthetase operon containing the genes bacA-bacC was cloned and sequenced, identifying a modular structure typical of peptide synthetases. The bacA gene product (BA1, 598kDa) contains five modules, with an internal epimerization domain attached to the fourth; bacB encodes BA2 (297kDa), and has two modules and a carboxy-terminal epimerization domain; bacC encodes BA3, five modules (723kDa) with additional internal epimerization domains attached to the second and fourth. A carboxy-terminal putative thioesterase domain was also detected in BA3. A putative cyclization domain was found in BA1 that may be involved in thiazoline ring formation. The adenylation/thioester-binding domains of the first two BA1 modules were overproduced and the detected amino-acid specificity coincides with the first two amino acids in bacitracin. Disruption of chromosomal bacB resulted in a bacitracin-deficient mutant. CONCLUSIONS: The genes encoding the bacitracin synthetases BA1, BA2 and BA3 are organized in an operon, the structure of which reflects the modular architecture expected of peptide synthetases. In addition, a putative thiazoline ring formation domain was identified in the BA1 gene.

Amino Acid Sequence↗

PubMed2002

[The VB system: a new modular osteosynthesis material involving both screws and wires].

VB is an osteosynthesis system for the stabilisation of small fragments, which combines the benefits of both wires and screws. It is a modular system comprising a threaded pin and a ring. The threaded pin is first positioned. Then a ring is grasped and opened by the progressive angulation of a screwdriver. Still anchored on the screwdriver, the ring slides easily on the pin. It is clamped on the pin by simply removing the screwdriver and the pin is then cut. This modular system includes 1.8 and 1.1 mm pins and different types of rings (threaded or non threaded, with or without collars). The system is easy to handle and can be introduced using an open or percutaneous technique, allowing compression or distraction. Our preliminary series, performed in accordance with National clinical trial protocol (Huriet) consisted of 50 cases in 24 patients (five women and 19 men) with an average age of 48 years, and a follow-up of more than six months. Fourteen cases of fractures (28 implants) were treated as emergencies (two radial heads, one capitellum, one trochlea of the humerus, seven distal radius fractures, one trapezium, two metacarpals) and 12 cases (22 implants) were elective cases: arthrodesis (one trapezo-metacarpal, one intermetacarpal, two interphalangeal, two carpal), non-union (six scaphoids, one phalangeal) and one phalangeal malunion. Hardware removal was performed in 16 cases. No implant failure has been detected. One case, a DIP arthrodesis, had a suspicion of sepsis which led to the removal of the implants at six weeks. The results of this study have convinced us of the merits of the system, which combines the advantages of both wires and screws. The system allows the user to perform either distraction or compression, and to adjust the force by hand. Compared to the fixed amount of compression produced by lag screws, this feature seems to be a real step forward.

Adult↗

PubMed2005

Self-assembled TNT biosensor based on modular multifunctional surface-tethered components.

We demonstrate a self-assembled reagentless biosensor based on a modular design strategy that functions in the detection of TNT and related explosive compounds. The sensor consists of a dye-labeled anti-TNT antibody fragment that interacts with a cofunctional surface-tethered DNA arm. The arm consists of a flexible biotinylated DNA oligonucleotide base specifically modified with a dye and terminating in a TNB recognition element, which is an analogue of TNT. Both of these elements are tethered to a Neutravidin surface with the TNB recognition element bound in the antibody fragment binding site, bringing the two dyes into proximity and establishing a baseline level of fluorescence resonance energy transfer (FRET). Addition of TNT, or related explosive compounds, to the sensor environment alters FRET in a concentration-dependent manner. The sensor can be regenerated repeatedly through washing away of analyte and specific reformation of the sensor assembly, allowing for subsequent detection events. Sensor dynamic range can be usefully altered through the addition of a DNA oligonucleotide that hybridizes to a portion of the cofunctional arm. The modular design of the sensor demonstrates that it can be easily adapted to detect a variety of different analytes.

Biosensing Techniques↗

PubMed2001

Enzymes of sphingolipid metabolism: from modular to integrative signaling.

Many enzymes of sphingolipid metabolism are regulated in response to extra- and intracellular stimuli and in turn serve as regulators of levels of bioactive lipids (such as sphingosine, ceramide, sphingosine 1-phosphate, and diacylglycerol), and as such, they serve a prototypical modular function in cell regulation. However, lipid metabolism is also closely interconnected in that a product of one enzyme serves as a substrate for another. Moreover, many cell stimuli regulate more than one of these enzymes, thus adding to the complexity of regulation of lipid metabolism. In this paper, we review the status of enzymes of sphingolipid metabolism in cell regulation and propose a role for these enzymes in integration of cell responses, a role that builds on the modular organization while also taking advantage of the complexity and interconnectedness of lipid metabolism, thus providing for a combinatorial mechanism of generating diversity in cell responses. This may be a general prototype for the involvement of metabolic pathways in cell regulation.

Acyltransferases↗

PubMed1997

Cobalamin-dependent methionine synthase is a modular protein with distinct regions for binding homocysteine, methyltetrahydrofolate, cobalamin, and adenosylmethionine.

Methionine synthase (MetH) catalyzes the transfer of a methyl group from bound methylcobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. The cofactor is then remethylated by methyltetrahydrofolate. We now demonstrate that MetH is able to catalyze methylation of free cob(I)alamin with methyltetrahydrofolate. MetH had previously been shown to catalyze methylation of homocysteine with free methylcobalamin as the methyl donor, in a reaction that is first-order in added methylcobalamin, and we have confirmed this observation using homogenous enzyme. A truncated polypeptide lacking the cobalamin-binding region of the holoenzyme, MetH(2-649), was overexpressed and purified to homogeneity. MetH(2-649) catalyzes the methylation of free cob(I)alamin by methyltetrahydrofolate and the methylation of homocysteine by free methylcobalamin. Furthermore, a protein comprising residues 2-353 of the holoenzyme has now been overexpressed and purified to homogeneity, and this protein catalyzes methyl transfer from free methylcobalamin to homocysteine but not from methyltetrahydrofolate to free cob(I)alamin. The mutations Cys310Ala and Cys311Ala in MetH(2-649) completely abolish methyl transfer from exogenous methylcobalamin to homocysteine but do not affect methyl transfer from methyltetrahydrofolate to exogenous cob(I)alamin, consistent with a modular construction for MetH. We infer that MetH is a modular protein comprising four separate regions: a homocysteine binding region (residues 2-353), a methyltetrahydrofolate binding region (residues 354-649), a region responsible for binding the cobalamin prosthetic group (residues 650-896), and an AdoMet-binding domain (residues 897-1227).

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed1999

Dissecting the role of acyltransferase domains of modular polyketide synthases in the choice and stereochemical fate of extender units.

Modular polyketide synthases (PKSs), such as the 6-deoxyerythronolide B synthase (DEBS), are large multifunctional enzyme complexes that are organized into modules, where each module carries the domains needed to catalyze the condensation of an extender unit onto a growing polyketide chain. Each module also dictates the stereochemistry of the chiral centers introduced into the backbone during the chain elongation process. Here we used domain mutagenesis to investigate the role of the acyl transferase (AT) domains of individual modules in the choice and stereochemical fate of extender units. Our results indicate that the AT domains of DEBS do not influence epimerization of the (2S)-methylmalonyl-CoA extender units. Hence, stereochemical control of the methyl-branched centers generated by DEBS most likely resides in the ketosynthase (KS) domains of the individual modules. In contrast, several recent studies have demonstrated that extender unit specificity can be altered by AT domain substitution. In some of these examples, the resulting polyketide was produced at considerably lower titers than the corresponding natural product. We analyzed one such attenuated mutant of DEBS, in which the methylmalonyl transferase domain of module 2 was replaced with a malonyl transferase domain. As reported earlier, the resulting PKS produced only small quantities of the expected desmethyl analogue of 6-deoxyerythronolide B. However, when the same hybrid module was placed as the terminal module in a truncated 2-module PKS, it produced nearly normal quantities of the expected desmethyl triketide lactone. These results illustrate the limits to modularity of these multifunctional enzymes. To dissect the role of specific amino acids in controlling AT substrate specificity, we exchanged several segments of amino acids between selected malonyl and methylmalonyl transferases, and found that a short (23-35 amino acid) C-terminal segment present in all AT domains is the principal determinant of their substrate specificity. Interestingly, its length and amino acid sequence vary considerably among the known AT domains. We therefore suggest that the choice of extender units by the PKS modules is influenced by a "hypervariable region", which could be manipulated via combinatorial mutagenesis to generate novel AT domains possessing relaxed or altered substrate specificity.

Acyl Coenzyme A↗

PubMed2006

Clearing the skies over modular polyketide synthases.

Modular polyketide synthases (PKSs) are large multifunctional proteins that synthesize complex polyketide metabolites in microbial cells. A series of recent studies confirm the close protein structural relationship between catalytic domains in the type I mammalian fatty acid synthase (FAS) and the basic synthase unit of the modular PKS. They also establish a remarkable similarity in the overall organization of the type I FAS and the PKS module. This information provides important new conclusions about catalytic domain architecture, function, and molecular recognition that are essential for future efforts to engineer useful polyketide metabolites with valuable biological activities.

Animals↗

PubMedDate not supplied

Part 1. modular approach to obtaining diverse tetrahydroquinoline-derived polycyclic skeletons for use in high-throughput generation of natural-product-like chemical probes.

A practical synthesis of a tetrahydroaminoquinoline scaffold (12) was developed that used a stereocontrolled aza Michael as the key reaction. Three tetrahydroquinoline alkaloid-like, tricyclic derivatives 16, 18, and 19 with different medium to macrocyclic ring skeletons were obtained, using this scaffold as the starting material, in a modular manner. The macrocyclic compounds with an isolated olefin and an electron-deficient olefin were obtained by ring-closing metathesis approaches. Compounds 16 and 18 are unique and contain bridged 10- and 12-membered functionalized rings. The NMR studies of these compounds revealed interesting information on the conformation of the bicyclic scaffolds that was dependent on the nature and the size of the macrocyclic rings. Finally, this modular methodology, using compound 21 anchored onto the solid support, successfully led to the generation of different macrocyclic derivatives, 23, 25, and 27 in solid-phase synthesis. The solid-phase synthesis approach outlined in this article has the potential to generate tetrahydroquinoline-based tricyclic compounds containing different medium to macrocyclic architectures.

Alkaloids↗

PubMedDate not supplied

Solution- and solid-phase, modular approaches for obtaining different natural product-like polycyclic architectures from an aminoindoline scaffold for combinatorial chemistry.

With the goal of developing a modular approach leading to different indoline alkaloid natural-product-like tricyclic derivatives having an unsaturated lactam (see compounds 13, 14, and 16), an aminoindoline-based bicyclic scaffold 10 was obtained from 9. The selective deprotection of the indoline NTeoc or benzylic NHAlloc in compound 10, followed by N-acryloylation and then subjection to a ring-closing metathesis reaction, successfully led to obtaining two different architectures (13/14 and 16) having an unsaturated lactam functionality. This modular solution-phase methodology was then developed on solid phase. To achieve this objective, the aminoindoline bicyclic scaffold having an additional hydroxyl group could be immobilized onto the solid support using alkylsilyl linker-based polystyrene macrobeads, giving 18. By applying a ring-closing metathesis approach, 20 (tricyclic derivative with seven-membered-ring unsaturated lactam) and 23 (tricyclic derivative with eight-membered-ring unsaturated lactam) were then obtained from 18 in a number of steps.

Combinatorial Chemistry Techniques↗

PubMed2002

The preparation of all-trans uniformly (13)C-labeled retinal via a modular total organic synthetic strategy. emerging central contribution of organic synthesis toward the structure and function study with atomic resolution in protein research.

Uniformly [(13)C(20)]-labeled all-trans-retinal (1) has been prepared via a convergent modular total organic strategy with high isotope incorporation (>99%) and without isotope dilution starting from commercially available 99% enriched (13)C-labeled starting materials. For this purpose we have developed a strategy that is based on four different modules: [1,2,3,4,(3-CH(3))-(13)C(5)]-4-(diethylphosphono)-3-methyl-2-butenenitrile (3), [1,2,3,4-(13)C(4)]-ethyl acetoacetate (7), [U-(13)C(5)]-4-bromo-2-methyl-2-butene (13), and [U-(13)C(10)]-2,6,6-trimethylcyclohex-2-ene-1-ylcarbonitrile (16). This scheme permits the synthesis of the full cassette of all isotopomers with (13)C-labels at any position or combination of positions by using different (13)C-labeled starting materials. In addition, modifications of the synthesized modules will give access to a broad range of chemically modified (13)C-labeled retinoids and carotenoids. This modular strategy enables the synthesis of multifold and uniformly stable isotopically labeled (bio)macromolecules that can be used for studying proteins with atomic resolution, providing detailed functional information of the studied biological system.

Carbon Isotopes↗

PubMed2004

Synthesis and single-molecule studies of a well-defined biomimetic modular multidomain polymer using a peptidomimetic beta-sheet module.

In the pursuit of advanced biomaterials with combined strength, toughness, and elasticity, a new class of well-defined modular polymers has been synthesized, and their nanomechanical properties have been studied using atomic force microscopy. These polymers are based on a peptidomimetic beta-sheet-based double-closed loop (DCL) module, which was designed to overcome the limitation of the modular polymers we reported previously (J. Am. Chem. Soc. 2004, 126, 2059). Single-molecule force-extension experiments revealed the sequential unfolding of these modules as the polymer is stretched, resulting in more regular sawtooth-patterned curves similar to those seen in titin and other biopolymers. The single-molecule data agreed well with computer modeling, which suggested that hydrogen bonding and pi-stacking are both involved in the formation of small DCL clusters along the polymer chain.

Biomimetic Materials↗