Cytochrome P450 2D6 is a heme-containing enzyme that is responsible for the metabolism of at least 20% of known drugs. Substrates of 2D6 typically contain a basic nitrogen and a planar aromatic ring. The crystal structure of human 2D6 has been solved and refined to 3.0 Å resolution. The structure shows the characteristic P450 fold as seen in other members of the family, with the lengths and orientations of the individual secondary structural elements being very similar to those seen in 2C9. There are, however, several important differences, the most notable involving the F helix, the F-G loop, the B helix, ␤ sheet 4, and part of ␤ sheet 1, all of which are situated on the distal face of the protein. The 2D6 structure has a well defined active site cavity above the heme group, containing many important residues that have been implicated in substrate recognition and binding, including Asp-301, Glu-216, Phe-483, and Phe-120. The crystal structure helps to explain how Asp-301, Glu-216, and Phe-483 can act as substrate binding residues and suggests that the role of Phe-120 is to control the orientation of the aromatic ring found in most substrates with respect to the heme. The structure has been compared with published homology models and has been used to explain much of the reported site-directed mutagenesis data and help understand the metabolism of several compounds. The cytochromes P4504 constitute a superfamily of heme-containing enzymes that catalyze the metabolism of a wide variety of endogenous and xenobiotic compounds. This is accomplished through the activation of molecular oxygen by the heme group, a process that involves the delivery of two electrons to the P450 system followed by cleavage of the dioxygen bond, yielding water and an activated iron-oxygen species (Compound 1), which reacts with substrates through a variety of mechanisms (1). In eukaryotic species, the electron source is a single flavoprotein, the FAD/FMN-containing cytochrome P450 reductase, which binds to the largely basic proximal face of the cytochrome through a number of salt bridges. Of the known human isoforms, cytochrome P450 2D6 is responsible for the metabolism of at least 20% of known drugs (2), with only 3A4 being responsible for a higher (50%) percentage.The cDNA encoding human P450 2D6 has been characterized (3) and subsequently localized to chromosome 22 in the q13.1 region (4). A relatively large number of genetic polymorphisms have been described for 2D6, some of which can either result in rapid or very poor metabolism. One well characterized allelic variant is responsible for a condition known as debrisoquine/sparteine type polymorphism (5, 6). This arises as a result of various genetic mutations and affects a significant percentage of the Caucasian population (7). It results in the defective metabolism of a number of important drug molecules, including debrisoquine, from which the condition got its name. The inability of patients to turn over compounds such as debrisoquine eventually leads to toxic levels of the drug in t...

Fibroblast activation protein ␣ (FAP␣) is highly expressed in epithelial cancers and has been implicated in extracellular matrix remodeling, tumor growth, and metastasis. We present the first high resolution structure for the apoenzyme as well as kinetic data toward small dipeptide substrates.

This paper draws on material entropy and life cycle thinking to develop the Resource States framework. This framework clarifies and systematises the language around resources within the circular economy (CE) discourse, such that insights from different tools and approaches that investigate different aspects of CE can be aggregated and a more comprehensive picture of complex circular systems can be compiled. Currently, progress of the CE discourse is hampered by a lack of a clear and systematic approach to what we refer to as the particles state and the products state. That is: whether to approach resource circulation from the perspective of elements, molecules or materials; or whether to adopt the perspective of products or finished goods. As these two perspectives are often implicit in current contributions to CE, we first articulate both approaches, before assessing their respective contributions and limitations. Next, we draw on material entropy and life cycle thinking to integrate both perspectives and develop a more comprehensive way of conceptualising resource states, in the form of the Resource States framework. We furthermore present how this framework can be used A) to clearly distinguish between circular strategies, as well as between different implementation scenarios of the same circular strategy; B) to systematically explore and map synergies and trade-offs between combinations of circular strategies; and C) to link circular strategies with structural waste present in a given context. Lastly, we discuss the strengths and weaknesses of the framework and reflect on how it advances the CE field.

Conceptualizing firms from a business ecosystem, value‐ or supply‐network perspective captures the boundary‐spanning nature of value creation. However, the relationship dynamics that enable or inhibit sustainable value creation, as well as the understanding of how to resolve trade‐offs in sustainable supply chain management, need to be better understood. To explore these, we present a comparative case study of how situational logics and power relations are embedded in business models within a UK brewer and its malt supply chain. The exploratory case illustrates how network‐centric business model innovation resolves the trade‐off between economic and environmental value through the prioritization of sustainability‐related ‘cultural’ resources. These findings suggest that organizations seeking to implement sustainable supply networks need to pay greater attention to how they use business model innovation to institutionalize situational logics that enable or inhibit sustainable value creation and resolve trade‐offs.

Molecular shape and electrostatic distribution play a crucial role in enzyme and receptor recognition and contribute extensively to binding affinity. Molecular similarity and bioisosterism are much-discussed topics in medicinal chemistry. Many molecular representations and similarity metrics are available to help drug discovery, and activities such as compound hit explosion and library design can be undertaken using them. The quality of the resulting compound series is highly dependent upon the molecular representation and similarity metric used. We have used a range of software to investigate whether molecules can be represented and compared effectively using measures of three-dimensional shape and electrostatic distribution ("electroforms"). We find that these descriptors allow for the assessment of molecular similarities using standard molecular visualization tools and offer a method for comparing molecules that may be considered superior to other methods.