Symmetric Grothendieck polynomials, skew Cauchy identities, and dual filtered Young graphs

Symmetric Grothendieck polynomials are analogues of Schur polynomials in the K-theory of Grassmannians. We build dual families of symmetric Grothendieck polynomials using Schur operators. With this approach we prove skew Cauchy identity and then derive various applications: skew Pieri rules, dual filtrations of Young's lattice, generating series and enumerative identities. We also give a new explanation of the finite expansion property for products of Grothendieck polynomials

Deciphering Functions of Intracellular Formaldehyde - Linking Cancer and Aldehyde Metabolism

[First paragraph]Formaldehyde, the simplest aldehyde, is an environmental pollutant and human toxin. Acute exposure to exogenous formaldehyde can cause irritation, nausea, renal failure, and coma. Chronic formaldehyde exposure correlates with increased cancer incidence, in particular of nasopharyngeal cancer and leukemia. In addition to exogenous sources, formaldehyde is produced endogenously in cells; eukaryotic pathways producing formaldehyde include xenobiotic metabolism and enzyme-catalyzed N-methyl demethylation of the N-methylated histone and DNA components of chromatin, as well as of RNA. Thus, endogenously produced formaldehyde may have biological roles; there have been very few studies connecting the biochemistry of formaldehyde with physiology

Deciphering Functions of Intracellular Formaldehyde - Linking Cancer and Aldehyde Metabolism

[First paragraph]Formaldehyde, the simplest aldehyde, is an environmental pollutant and human toxin. Acute exposure to exogenous formaldehyde can cause irritation, nausea, renal failure, and coma. Chronic formaldehyde exposure correlates with increased cancer incidence, in particular of nasopharyngeal cancer and leukemia. In addition to exogenous sources, formaldehyde is produced endogenously in cells; eukaryotic pathways producing formaldehyde include xenobiotic metabolism and enzyme-catalyzed N-methyl demethylation of the N-methylated histone and DNA components of chromatin, as well as of RNA. Thus, endogenously produced formaldehyde may have biological roles; there have been very few studies connecting the biochemistry of formaldehyde with physiology

Mechanism of Molecular Oxygen Diffusion in a Hypoxia-Sensing Prolyl Hydroxylase Using Multiscale Simulation

The chronic response of animals to hypoxia is mediated by the αβ-heterodimeric hypoxia-inducible transcription factors (α,β-HIFs) which upregulate the expression of sets of genes that work to ameliorate the effects of limiting dioxygen. The HIF prolyl hydroxylase domain enzymes (PHDs) are Fe­(II)- and 2-oxoglutarate-dependent oxygenases that act as hypoxia-sensing components of the HIF system: prolyl-hydroxylation signals for dioxgen availability-dependent HIF-α degradation via the ubiquitin proteasome system. The unusual kinetic properties of the PHDs, in particular a high Km for dioxygen and slow reaction with dioxygen, are proposed to enable their hypoxia-sensing role. An understanding of how dioxygen is delivered to, and binds at, the active site of the PHDs is important for the development of a chemical understanding of the hypoxic response. We employed a combined multiscale approach involving classical atomistic equilibrium and nonequilibrium MD simulations combined with QM/MM trajectories to investigate dioxygen diffusion to, and binding at, the active site in the PHD2.Fe­(II).2OG.HIF substrate complex; PHD2 is the most important of the three human PHDs. The transport of dioxygen to the active site is described; dioxygen transport follows a single well-defined hydrophobic tunnel, formed from both enzyme and substrate elements to reach the PHD2 active site. The results provide estimates for rate constants that define a diffusion-reaction model for dioxygen:PHD2 interactions; in combination with reported biophysical analyses they provide chemical insight into the basis of the slow reaction of PHD2 with dioxygen. They imply that the reversible binding of dioxygen is central to the hypoxia-sensing capacity of the PHDs and that different PHD HIF-α substrate combinations might have different dioxygen sensitivity profiles. The extent of HIF-α substrate prolyl hydroxylation, which signals for subsequent HIF-α degradation, may thus be a manifestation of the equilibrium between dioxygen in bulk solution and dioxygen bound to the PHD2.Fe.2OG.HIF-α substrate complex

Methyl 6-amino-6-oxohexanoate

The title compound, C7H13NO3, adopts an approximately planar conformation. The torsion angles in the aliphatic chain between the carbonyl group C atoms range from 172.97 (14) to 179.38 (14)° and the r.m.s. deviation of all non-H atoms is 0.059 Å. The crystal packing is dominated by two strong N—H?O hydrogen bonds involving the amide groups and forming R22(8) rings and C(4) chains. Overall, a two-dimensional network parallel to (100) is formed. A weak inter­molecular C—H?O inter­action is also present.</p

3-Methoxy-3-oxopropanaminium chloride

In the title compound, C4H10NO2+·Cl-, the central ethyl­ene bond of the cation adopts a gauche conformation. The three H atoms of the -NH3+ group are engaged in strong and highly directional inter­molecular N-H...Cl hydrogen bonds, which result in a tape-like arrangement along [010] of the respective ion pairs. In addition, weak inter­molecular C-H...Cl and C-H...O inter­actions are present.</p

Methyl 6-amino-6-oxohexanoate

The title compound, C7H13NO3, adopts an approximately planar conformation. The torsion angles in the aliphatic chain between the carbonyl group C atoms range from 172.97 (14) to 179.38 (14)° and the r.m.s. deviation of all non-H atoms is 0.059 Å. The crystal packing is dominated by two strong N—H?O hydrogen bonds involving the amide groups and forming R22(8) rings and C(4) chains. Overall, a two-dimensional network parallel to (100) is formed. A weak inter­molecular C—H?O inter­action is also present.</p

3-Methoxy-3-oxopropanaminium chloride

In the title compound, C4H10NO2+·Cl-, the central ethyl­ene bond of the cation adopts a gauche conformation. The three H atoms of the -NH3+ group are engaged in strong and highly directional inter­molecular N-H...Cl hydrogen bonds, which result in a tape-like arrangement along [010] of the respective ion pairs. In addition, weak inter­molecular C-H...Cl and C-H...O inter­actions are present.</p

Chemical Basis for the Selectivity of the von Hippel Lindau Tumor Suppressor pVHL for Prolyl-Hydroxylated HIF-1α

In animals, the post-translational hydroxylation of hypoxia inducible factor (HIF) is a central mechanism for regulating gene expression in an oxygen-dependent manner. The oxygenase-catalyzed trans-4-prolyl hydroxylation of HIF-α increases its affinity for the von Hippel Lindau protein elongin B/C (VCB) ubiquitin ligase complex, leading to HIF-α degradation. The level of binding of HIF-α to VCB is increased by ∼1000-fold upon addition of a single oxygen atom to a conserved proline residue. Here, we describe computational studies on the chemical basis of this “switchlike” signaling event. The results support crystallographic analyses showing the importance of hydrogen bonding in the binding of hydroxylated HIF-α to VCB and suggest that trans 4-hydroxylation “preorganizes” the proline residue to adopt the C4-exo conformation, via operation of the stereoelectronic gauche effect

Figures S1 and S2; Table S1 from Inhibitors of both the <i>N</i>-methyl lysyl- and arginyl- demethylase activities of the JmjC oxygenases

Time course assays using LC-MS showing the extent of KDM (A) or RDM (B) demethylation.; Comparison of the KDM and RDM activities of KDM4E.; Kinetic parameters (KM, kcat and kcat/ KM)) for substrates and 2O