Chronic Pain Management in a CYP2D6 Poor Metabolizer: A Case Report for Oxycodone.

The objective of this case report is to illustrate pharmacogenomics (PGx)-guided oxycodone treatment, given the conflicting data on the analgesic response from oxycodone in Cytochrome P450 (CYP)2D6 poor metabolizers (PMs). PGx-guided therapy can help improve treatment outcomes. This case report describes a 58-year-old patient who was prescribed oxycodone for chronic pain management. The patient presented with a history of inadequate pain control despite analgesic treatment with oxycodone (morphine milliequivalent [MME] = 22.5). Pharmacogenetic testing revealed that the patient was a CYP2D6 Poor Metabolizer (PM), which may shed light on the observed lack of analgesic response to oxycodone. The clinical pharmacist recommended switching to an alternative opioid not metabolized via the CYP2D6 pathway. The patient was subsequently switched to hydromorphone (MME = 16), resulting in improved pain control and fewer side effects. The newer hydromorphone dose accounted for a 30% MME dose reduction. The patient's initial average and worst pain score were 7 and 9 out of 10, respectively, per the numeric rating scale (NRS). Upon follow-up with the patient in two weeks, her average and worst pain scores improved to 3 and 3.5 out of 10, respectively, per the NRS. Further PGx testing results led to an overall positive outcome, such as her willingness to participate in physical therapy as a result of improved pain scores. This case highlights the importance of considering individual variability in drug metabolism when prescribing medications, particularly opioids such as oxycodone, to ensure optimal therapeutic outcomes and minimize the risk of adverse events in CYP2D6 PMs.

Clustered hydrophobic amino acids in amphipathic helices mediate erlin1/2 complex assembly.

Erlin1 and erlin2 are highly homologous, ∼40kDa, endoplasmic reticulum membrane proteins that assemble into a ring-shaped complex with a mass of ∼2 MDa. How this complex is formed is not understood, but appears to involve multiple interactions, including a coiled-coil region that mediates lower-order erlin assembly, and a short hydrophobic region, termed the "assembly domain", that mediates higher-order assembly into ∼2 MDa complexes. Here we have used molecular modeling, mutagenesis and cross-linking to examine the role of the assembly domain in higher-order assembly. We find (i) that the assembly domains of erlin1 and erlin2 are amphipathic helices, (ii) that erlin1 alone and erlin2 alone can assemble into ∼2 MDa complexes, (iii) that higher-order assembly is strongly inhibited by point mutations to the assembly domain, (iv) that three interacting hydrophobic residues in the assembly domain and aromaticity are essential for higher-order assembly, and (iv) that while erlins1 and 2 are equally capable of forming lower-order homo- and hetero-oligomers, hetero-oligomers are the most prevalent form when erlin1 and erlin2 are co-expressed. Overall, we conclude that the ∼2 MDa erlin1/2 complex is composed of an assemblage of lower-order hetero-oligomers, probably heterotrimers, linked together by assembly domain hydrophobic residues.

Protein homomers in point-group assembly: symmetry making and breaking are specific and distinctive in their codes of chemical alphabet in side chains.

Oligomerizing to point-group symmetry, protein oligomers need to have the symmetry broken for biologically crucial functions, such as, allosteric regulation, enzyme catalysis, and so forth. In the making of symmetry, based on self assembly, and the breaking of symmetry, based on intermolecular interactions, proteins may manifest, like their other functions, specific scripts over the coding alphabet in side chains. To address the possibility, we analyzed 82 protein homodimers in their C(2)-symmetry-related side chains across noncrystallographic interfaces, to know if they may be identical or distinct in conformation, and thus conserved or broken in symmetry. We find the propensity to conformational mismatch across interfaces correlated with side-chain chemical structure, low to very low in aromatic Trp, Tyr, His, Phe, and Arg, and high to very high in aliphatic Val, Pro, Met, Glu, Ser, Lys, Gln, Asn, and Asp, related not to polarity but, interestingly, to aromaticity of the structure. The organizational plan having aromatics embedded in a hub of aliphatic-nonpolar groups and a surrounding rim of aliphatic-polar groups, called "hotspot," has been known to direct protein-protein interaction. Finding conformational-mismatch propensities of side chains congruous with their specific chemical roles in protein-protein interaction, we propose that aromatic side chains will drive protein homomers to high symmetry, while polar- and nonpolar aliphatic side chains will drive them to the functionally-necessitated breaks of symmetry. Side chains are in their roles as protein-coding alphabet illuminated in the physics, which is discussed.

Electrostatics-defying interaction between arginine termini as a thermodynamic driving force in protein-protein interaction.

Apparent electrostatics-defying clustering of arginines attributed as screening effect of solvent is in this study examined as a possible thermodynamic driving force in protein-protein interaction. A dataset of 266 protein dimers is found to have approximately 22% arginines mutually paired and approximately 17% pairs in interaction across interfaces and thus putative "hotspots" of protein-protein interaction. The pairing, uncorrelated with inter or intramolecular context, could be contributing in protein folding as well, and, uncorrelated with solvent access, could be driven by effects that are generic to solvent and protein structures. Mutually stacked at shorter distances but in diverse geometrical modes otherwise, the cations tend to be in gross deficit of hydrogen-bond partners, and contributing electrostatics across protein-protein interface that, on average, is repulsive for protein-protein interaction. Embedded in local environment enriched in polarizable residues, aromatic, aliphatic, and anionic, the arginines may contribute to protein-protein interaction via environmental polarization response to electrostatics of cation clustering, a possible new principle in molecular recognition.