- Determinant of Ser-Thr protein kinase specificity is identified
- How does methylcyanobutadiyne form in space?
- Maximize the strength of cellulose nanocrystals
- Nanoparticles preserve medieval bones
- These quantum dots have humble origins
- Use supercritical carbon dioxide to clean banknotes
- Optimize an asymmetric hydrogenation reaction
A major determinant of serine–threonine protein kinase specificity is identified. Protein kinases chemically modify other proteins by adding phosphate groups to them at defined sites. For phosphorylation to occur, the substrate residue must bind transiently to the catalytic cleft within the kinase. Accordingly, protein kinases usually phosphorylate substrates in consensus sequence motifs that are complementary to the kinase active site. These site motifs help target kinases to substrates and specific phosphorylation residues.
Eukaryotic protein kinases are thought to be tyrosine- or serine–threonine (Ser-Thr)–specific. Many Ser-Thr kinases have a significant preference for serine or threonine as the phosphoacceptor residue. This selectivity cannot be determined through phylogeny (evolutionary history), and its mechanism is unknown.
B. E. Turk and collaborators at Yale University (New Haven, CT), the Chinese University of Hong Kong (Shatin), Fox Chase Cancer Center (Philadelphia), the University of Toronto, Oxford University (UK), and the Ludwig Institute for Cancer Research (Oxford) show that the phosphoacceptor preference of Ser-Thr kinases is determined by a single residue located in the kinase activation segment that is immediately downstream of a conserved Asp-Phe-Gly sequence (DFG) and the N terminus of the kinase activation loop.
At this “DFG+1” position, serine-selective kinases have larger hydrophobic residues, and threonine-specific kinases have β-branched aliphatic residues. Mutating this lone residue in the substrate binding cleft can invert the phosphorylation site specificity for serine- or threonine-specific kinases. Structural data demonstrate that active site binding affinity is not important for determining phosphoacceptor preference; the key factor is to establish conformations that are optimal for phosphate transfer and catalysis.
Although identifying additional modifier residues will allow a more complete understanding of the structural features of kinase specificity, the data in this report show that the DFG+1 residue plays a predominant role in determining phosphoacceptor specificity. When this residue is sequenced, phosphorylation site preference can be predicted, and kinases of unknown selectivity can be classified. (Mol. Cell 2014, 53, 140–147; Abigail Druck Shudofsky)
How does the exotic molecule methylcyanobutadiyne form in space? Cyanopolyynes and their analogues (e.g., methylcyanopolyynes) are linear N-heterohydrocarbons that are found in the interstellar medium (ISM). Their composition and structure make them ideal precursors for building blocks of life, including amino acids, purines, and pyrimidines, through abiotic synthesis.
Y. Trolez, J.-C. Guillemin, and coauthors at the National School of Chemistry Rennes, the European University of Brittany (Rennes), and the University of Rennes 1 (all in France) improved the synthetic route to methylcyanobutadiyne (1), the largest member of its family to have been detected in the ISM. They also used photolysis experiments to identify a tentative pathway for the formation of 1 in the ISM.
The researchers began with commercially available 1,4-dichloro-2-butyne, which they converted to amide 2 in three steps (see Figure 1). Dehydrating 2 under vacuum in the presence of P4O10 and sand gave 1 in 36% yield. This strategy also was applied to the synthesis of cyanobutadiyne (3) from the corresponding amide.
The authors then photolyzed of a variety of potential precursors to simulate the conditions that form 1 in the ISM. They found that the ·C3N radical from cyanoacetylene can couple with propyne to produce 1 (see Figure 2).
Control cellulose nanocrystal dimensions to maximize their strength. Because of their high modulus values, cellulose nanocrystals (CNCs) are studied as dynamic reinforcing elements in numerous polymeric matrices. S. Keten and colleagues at Northwestern University (Evanston, IL) investigated the influence of crystal dimensions and defects on the mechanical properties of CNCs.
The researchers used atomistic simulations to examine the fracture strength as a function of the dimensions of a model monoclinic 1β CNC, particularly along the weakest plane, . They used steered molecular dynamics to obtain a free-energy analysis for the interactions between CNCs, which allowed them to quantify the CNCs’ fracture energies. An analysis of hydrogen-bonding occupancy and fracture strength as a function of CNC size showed that edge defects play a larger role in smaller width CNCs. This causes smaller CNCs to have lower fracture strength and stability than larger ones.
The authors determined that the fracture strength depends strongly on CNC thickness up to a ≈4-fold increase. Beyond that point, fracture strength levels off as a result of scaling of the van der Waals interactions along the  plane. When the role of surface/volume ratio for interfacial strength was considered in addition to maximum fracture strength, the authors obtained an optimal CNC dimension of 6.2–7.3 nm wide by 4.8–5.6 nm thick. (ACS Macro Lett. 2014, 3, 64–69; LaShanda Korley)
Nanoparticles preserve medieval bones. Although ancient bones decay more slowly than soft tissues, they eventually demineralize by a process similar to osteoporosis. Archaeologists and paleontologists use various methods for preserving fragile old bones for transport and study, many that involve filling the pores with vinyl or acrylic polymers. But this can lead to problems with compatibility, reversibility, and stability.
P. Baglioni, L. Dei, and co-workers at the University of Florence (Italy) devised a way to grow aragonite-polymorph CaCO3 crystals in situ in bone remains, thereby increasing bone strength by 50–70%. They used the collagen present in the remains, atmospheric CO2, and Ca(OH)2 nanoparticles. They note that although the aragonite polymorph is less stable than calcite, it has greater mechanical strength.
Bone fragments from the late Middle Ages were obtained from a parish church in Milan as part of a restoration project. The authors confirmed that the bone samples contained enough collagen to promote the formation of the aragonite polymorph. The bones were conserved in a closed shrine, which limited their contact with external biological agents that could have degraded the collagen.
They treated the bones in a room of the church that had climatic conditions similar to the shrine in which the relics were kept, including a relative humidity of ≈75%. They immersed the bone fragments in a commercially produced suspension of Ca(OH)2 nanoparticles in i-PrOH. When the solvent evaporated, a fresh batch of the suspension was applied. They repeated the process 10 times over 3 months.
Ordinarily, the alkaline environment in the vicinity of the Ca(OH)2 nanoparticles would have denatured the collagen during treatment, but with i-PrOH instead of water as the suspending liquid, the speed of the carbonation reaction reduced the extent of collagen hydrolysis.
The authors confirmed the complete carbonation of the nanoparticles by using scanning electron microscopy and Fourier transform IR spectroscopy. The samples were further characterized with a variety of chemical, mechanical, and structural analytical techniques. The authors verified that a new crystalline carbonate matrix had not only formed on the surface, but it acted as a binder and filler inside the original weakened porous substrate.
The figure shows microtomography sections of untreated (left) and treated bone fragments. The arrows indicate the front surface of each fragment.
The carbonate crystals prevented the bone fragments from further flaking and powdering, and they were physically and chemically compatible with the bone substrate. The process is easy and cost-effective. An added benefit is the antimicrobial protection offered by the nanoparticle suspension. (Langmuir 2014, 30, 660–668; Nancy McGuire)
These quantum dots have humble origins. Graphene quantum dots (GQDs) are nanosized graphene particles with valuable optical and electronic properties. GQDs are manufactured from carbon-based precursors ranging from glucose to carbon nanotubes, often with low yields at a relatively high cost. Coal, an abundant carbon source, has not been used as a starting material for GQDs.
J. M. Tour and colleagues at Rice University (Houston) recognized that the dominant component of coal is covalently connected nanosized crystalline carbon. They developed a simple strategy for transforming coal into GQDs by breaking down the covalent linkages under oxidizing conditions.
The authors chose three types of coal: anthracite, bituminous coal, and coke. In all of them, crystalline carbon domains are linked by aliphatic carbon chains. Coal samples suspended in a mixture of concentrated H2SO4 and HNO3 were subjected to cup sonication for 2 h, then heated for 24 h. After NaOH neutralization, the inorganic salts were removed by dialysis. Removing water produced GQDs in up to 20% isolated yield. Under the same conditions, commercial flake graphite did not yield GQDs because converting its purely sp2 carbon-based structure requires harsher conditions.
GQDs derived from bituminous coal (2.96 ± 0.96 nm diam) and coke (5.8 ± 1.7 nm diam) were smaller than those obtained from anthracite (29 ± 11 nm diam). All three types of GQDs exhibited pH-dependent photoluminescence as a result of pH-modulated aggregation.
Use supercritical carbon dioxide to clean banknotes. Central banks around the world must dispose of ≈150,000 tons of banknotes annually at a cost of US$150 billion. The major reason for removing banknotes from circulation is soiling caused by the transfer of human sebum to note surfaces followed by oxidation that turns the notes yellow. N. M. Lawandy* and A. Smuk at Spectra Systems and at Brown University (both in Providence, RI) used supercritical CO2 (scCO2) to clean banknotes and allow their reuse.
In their study, the authors used banknotes soiled during circulation and clean notes that were artificially soiled with motor oil or Bey sebum (a mixture of beef tallow and other fatty compounds) and then oxidized. They exposed the notes to scCO2 at 60 ºC and 2000 psi pressure for 16 h in a pressure vessel (see figure ). An inspection of the notes showed that the treatment removed oxidized sebum, oils, and even microorganisms; but security features such as fluorescent, magnetic, and UV light–responsive inks were not affected. The process succeeded even when the notes were wrapped with conventional 100-note straps used by banks. It works with paper and polymer banknotes.
The authors successfully tested their process with several denominations of US dollar notes ($1, $5, $20, and $100), British pound notes, euros, Indian rupees, and Russian rubles. The method may significantly reduce central bank operating costs and mitigate the environmental impact of note disposal. (Ind. Eng. Chem. Res. 2014, 53, 530–540; José C. Barros)
Optimize an asymmetric hydrogenation reaction. (R)-2-(3-Chloro-4-methanesulfonylphenyl)-3-cyclopentylpropionic acid with ³95% ee is a key building block in the synthesis of a glucokinase activator for treating type 2 diabetes. S. Bachmann and co-workers at F. Hoffman-La Roche (Basel, Switzerland) synthesized the intermediate by asymmetrically hydrogenating the dicyclohexylamine salt of 2-(3-chloro-4-methanesulfonylphenyl)-3-cyclopentylacrylic acid.
The authors screened several rhodium and iridium catalyst systems and 140 ruthenium-based catalysts. They chose a MeOBIPHEP-type ruthenium catalyst that worked well in MeOH solvent for scale-up. [MeOBIPHEP is 5,5′-dichloro-6,6'-dimethoxy-1,1'-biphenyl-2,2'-diylbis(diphenylphosphine).]
The authors show that the geometry of the double bond in the starting material is crucial. Material with an 80:20 E/Z ratio gave a product with only 8.4% ee, whereas pure E-isomer gave 90% ee.
At the end of the reaction, the mixture was a thick suspension that was difficult to remove from the autoclave. This problem was solved by adding aq H2SO4. The enantiopurity of the crude product was upgraded to 97% ee by recrystallizing it from i-PrOH. (Org. Process Res. Dev. 2013, 17, 1451–1457; Will Watson)