Conventional optical components are limited to size scales much larger than the wavelength of light, as changes to the amplitude, phase and polarization of the electromagnetic fields are accrued ...gradually along an optical path. However, advances in nanophotonics have produced ultrathin, so-called 'flat' optical components that beget abrupt changes in these properties over distances significantly shorter than the free-space wavelength. Although high optical losses still plague many approaches, phonon polariton (PhP) materials have demonstrated long lifetimes for sub-diffractional modes in comparison to plasmon-polariton-based nanophotonics. We experimentally observe a threefold improvement in polariton lifetime through isotopic enrichment of hexagonal boron nitride (hBN). Commensurate increases in the polariton propagation length are demonstrated via direct imaging of polaritonic standing waves by means of infrared nano-optics. Our results provide the foundation for a materials-growth-directed approach aimed at realizing the loss control necessary for the development of PhP-based nanophotonic devices.
Abstract
The aim of this randomized clinical trial was to evaluate the impact of all-
trans
retinoic acid (ATRA) in combination with non-intensive chemotherapy in older unfit patients (> 60 years) ...with newly diagnosed
NPM1
-mutated acute myeloid leukemia. Patients were randomized (1:1) to low-dose chemotherapy with or without open-label ATRA 45 mg/m
2
, days 8–28; the dose of ATRA was reduced to 45 mg/m
2
, days 8–10 and 15 mg/m
2
, days 11–28 after 75 patients due to toxicity. Up to 6 cycles of cytarabine 20 mg/day s.c., bid, days 1–7 and etoposide 100 mg/day, p.o. or i.v., days 1–3 with (ATRA) or without ATRA (CONTROL) were intended. The primary endpoint was overall survival (OS). Between May 2011 and September 2016, 144 patients (median age, 77 years; range, 64–92 years) were randomized (72, CONTROL; 72, ATRA). Baseline characteristics were balanced between the two study arms. The median number of treatment cycles was 2 in ATRA and 2.5 in CONTROL. OS was significantly shorter in the ATRA compared to the CONTROL arm (
p
= 0.023; median OS: 5 months versus 9.2 months, 2-years OS rate: 7% versus 10%, respectively). Rates of CR/CRi were not different between treatment arms; infections were more common in ATRA beyond treatment cycle one. The addition of ATRA to low-dose cytarabine plus etoposide in an older, unfit patient population was not beneficial, but rather led to an inferior outcome.
The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2010-023409-37, first posted 14/12/2010).
Flavin dependent monooxygenases Huijbers, Mieke M.E.; Montersino, Stefania; Westphal, Adrie H. ...
Archives of biochemistry and biophysics,
02/2014, Letnik:
544
Journal Article
Recenzirano
•Update of classification of flavin-dependent monooxygenases.•135 Family members divided in 8 groups.•Fifty percent of group members without EC number.•Flavin C4a-oxygen adduct not always oxygenation ...species.•First example of a naturally fused two-component flavin monooxygenase.
Flavin-dependent monooxygenases catalyze a wide variety of chemo-, regio- and enantioselective oxygenation reactions. As such, they are involved in key biological processes ranging from catabolism, detoxification and biosynthesis, to light emission and axon guidance. Based on fold and function, flavin-dependent monooxygenases can be distributed into eight groups. Groups A and B comprise enzymes that rely on NAD(P)H as external electron donor. Groups C–F are two-protein systems, composed of a monooxygenase and a flavin reductase. Groups G and H comprise internal monooxygenases that reduce the flavin cofactor through substrate oxidation. Recently, many new flavin-dependent monooxygenases have been discovered. In addition to posing basic enzymological questions, these proteins attract attention of pharmaceutical and fine-chemical industries, given their importance as regio- and enantioselective biocatalysts. In this review we present an update of the classification of flavin-dependent monooxygenases and summarize the latest advances in our understanding of their catalytic and structural properties.
Flavoprotein monooxygenases (FPMOs) are single- or two-component enzymes that catalyze a diverse set of chemo-, regio- and enantioselective oxyfunctionalization reactions. In this review, we describe ...how FPMOs have evolved from model enzymes in mechanistic flavoprotein research to biotechnologically relevant catalysts that can be applied for the sustainable production of valuable chemicals. After a historical account of the development of the FPMO field, we explain the FPMO classification system, which is primarily based on protein structural properties and electron donor specificities. We then summarize the most appealing reactions catalyzed by each group with a focus on the different types of oxygenation chemistries. Wherever relevant, we report engineering strategies that have been used to improve the robustness and applicability of FPMOs.
4-Hydroxybenzoate 3-hydroxylase (PHBH) is the most extensively studied group A flavoprotein monooxygenase (FPMO). PHBH is almost exclusively found in prokaryotes, where its induction, usually as a ...consequence of lignin degradation, results in the regioselective formation of protocatechuate, one of the central intermediates in the global carbon cycle. In this contribution we introduce several less known FAD-dependent 4-hydroxybenzoate hydroxylases. Phylogenetic analysis showed that the enzymes discussed here reside in distinct clades of the group A FPMO family, indicating their separate divergence from a common ancestor. Protein homology modelling revealed that the fungal 4-hydroxybenzoate 3-hydroxylase PhhA is structurally related to phenol hydroxylase (PHHY) and 3-hydroxybenzoate 4-hydroxylase (3HB4H). 4-Hydroxybenzoate 1-hydroxylase (4HB1H) from yeast catalyzes an oxidative decarboxylation reaction and is structurally similar to 3-hydroxybenzoate 6-hydroxylase (3HB6H), salicylate hydroxylase (SALH) and 6-hydroxynicotinate 3-monooxygenase (6HNMO). Genome mining suggests that the 4HB1H activity is widespread in the fungal kingdom and might be responsible for the oxidative decarboxylation of vanillate, an import intermediate in lignin degradation. 4-Hydroxybenzoyl-CoA 1-hydroxylase (PhgA) catalyzes an intramolecular migration reaction (NIH shift) during the three-step conversion of 4-hydroxybenzoate to gentisate in certain Bacillus species. PhgA is phylogenetically related to 4-hydroxyphenylacetate 1-hydroxylase (4HPA1H). In summary, this paper shines light on the natural diversity of group A FPMOs that are involved in the aerobic microbial catabolism of 4-hydroxybenzoate.
Display omitted
•Nature uses diverse group A flavoprotein monooxygenases for the catabolism of 4-hydroxybenzoate.•FAD-dependent 4-hydroxybenzoate hydroxylases differ in reaction mechanism and regioselectivity.•Update sequence relationship group A flavoprotein monooxygenases.•FAD-dependent 4-hydroxybenzoate hydroxylases separately diverged from a common ancestor.
Flavoprotein monooxygenases create valuable compounds that are of high interest for the chemical, pharmaceutical, and agrochemical industries, among others. Monooxygenases that use flavin as cofactor ...are either single- or two-component systems. Here we summarize the current knowledge about two-component flavin adenine dinucleotide (FAD)-dependent monooxygenases and describe their biotechnological relevance. Two-component FAD-dependent monooxygenases catalyze hydroxylation, epoxidation, and halogenation reactions and are physiologically involved in amino acid metabolism, mineralization of aromatic compounds, and biosynthesis of secondary metabolites. The monooxygenase component of these enzymes is strictly dependent on reduced FAD, which is supplied by the reductase component. More and more representatives of two-component FAD-dependent monooxygenases have been discovered and characterized in recent years, which has resulted in the identification of novel physiological roles, functional properties, and a variety of biocatalytic opportunities.
Amino groups derived from naturally abundant amino acids or (di)amines can be used as “shuttles” in nature for oxygen transfer to provide intermediates or products comprising N-O functional groups ...such as
N
-hydroxy, oxazine, isoxazolidine, nitro, nitrone, oxime,
C
-,
S
-, or
N
-nitroso, and azoxy units. To this end, molecular oxygen is activated by flavin, heme, or metal cofactor-containing enzymes and transferred to initially obtain
N
-hydroxy compounds, which can be further functionalized. In this review, we focus on flavin-dependent
N
-hydroxylating enzymes, which play a major role in the production of secondary metabolites, such as siderophores or antimicrobial agents. Flavoprotein monooxygenases of higher organisms (among others, in humans) can interact with nitrogen-bearing secondary metabolites or are relevant with respect to detoxification metabolism and are thus of importance to understand potential medical applications. Many enzymes that catalyze
N
-hydroxylation reactions have specific substrate scopes and others are rather relaxed. The subsequent conversion towards various N-O or N-N comprising molecules is also described. Overall, flavin-dependent
N
-hydroxylating enzymes can accept amines, diamines, amino acids, amino sugars, and amino aromatic compounds and thus provide access to versatile families of compounds containing the N-O motif. Natural roles as well as synthetic applications are highlighted.
Key points
• N-O and N-N comprising natural and
(
semi
)
synthetic products are highlighted
.
• Flavin-based NMOs with respect to mechanism
,
structure
,
and phylogeny are reviewed
.
• Applications in natural product formation and synthetic approaches are provided
.
Graphical abstract
.
Monooxygenases perform chemo‐, regio‐ and/or enantioselective oxygenations of organic substrates under mild reaction conditions. These properties and the increasing number of representatives along ...with effective preparation methods place monooxygenases in the focus of industrial biocatalysis. Mechanistic and structural insights reveal reaction sequences and allow turning them into efficient tools for the production of valuable products. Herein we describe two biocatalytically relevant subclasses of flavoprotein monooxygenases with a close evolutionary relation: subclass A represented by p‐hydroxybenzoate hydroxylase (PHBH) and subclass E formed by styrene monooxygenases (SMOs). PHBH family members perform highly regioselective hydroxylations on a wide variety of aromatic compounds. The more recently discovered SMOs catalyze a number of stereoselective epoxidation and sulfoxidation reactions. Mechanistic and structural studies expose distinct characteristics, which provide a promising source for future biocatalyst development.
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