Fatty Acid Binding Sites Research Articles

Necator americanus Ancylostoma Secreted Protein-2 (Na-ASP-2) Binds an Ascaroside (ascr#3) in Its Fatty Acid Binding Site.

During their infective stages, hookworms release excretory-secretory (E-S) products, small molecules, and proteins to help evade and suppress the host's immune system. Small molecules found in E-S products of mammalian hookworms include nematode derived metabolites like ascarosides, which are composed of the sugar ascarylose linked to a fatty acid side chain. The most abundant proteins found in hookworm E-S products are members of the protein family known as Ancylostoma secreted protein (ASP). In this study, two ascarosides and their fatty acid moieties were synthesized and tested for in vitro binding to Na-ASP-2 using both a ligand competition assay and microscale thermophoresis. The fatty acid moieties of both ascarosides tested and ascr#3, an ascaroside found in rat hookworm E-S products, bind to Na-ASP-2's palmitate binding cavity. These molecules were confirmed to bind to the palmitate but not the sterol binding sites. An ascaroside, oscr#10, which is not found in hookworm E-S products, does not bind to Na-ASP-2. More studies are required to determine the structural basis of ascarosides binding by Na-ASP-2 and to understand the physiological significance of these observations.

Allosterically Coupled Multisite Binding of Testosterone to Human Serum Albumin.

Human serum albumin (HSA) acts as a carrier for testosterone, other sex hormones, fatty acids, and drugs. However, the dynamics of testosterone's binding to HSA and the structure of its binding sites remain incompletely understood. Here, we characterize the dynamics of testosterone's binding to HSA and the stoichiometry and structural location of the binding sites using 2-dimensional nuclear magnetic resonance (2D NMR), fluorescence spectroscopy, 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid dipotassium salt partitioning, and equilibrium dialysis, complemented by molecular modeling. 2D NMR studies showed that testosterone competitively displaced 18-[13C]-oleic acid from at least 3 known fatty acid binding sites on HSA that also bind many drugs. Binding isotherms of testosterone's binding to HSA generated using fluorescence spectroscopy and equilibrium dialysis were nonlinear and the apparent dissociation constant varied with different concentrations of testosterone and HSA. The binding isotherms neither conformed to a linear binding model with 1:1 stoichiometry nor to 2 independent binding sites; the binding isotherms were most consistent with 2 or more allosterically coupled binding sites. Molecular dynamics studies revealed that testosterone's binding to fatty acid binding site 3 on HSA was associated with conformational changes at site 6, indicating that residues in in these 2 distinct binding sites are allosterically coupled. There are multiple, allosterically coupled binding sites for testosterone on HSA. Testosterone shares these binding sites on HSA with free fatty acids, which could displace testosterone from HSA under various physiological states or disease conditions, affecting its bioavailability.

The Minimal Effect of Linker Length for Fatty Acid Conjugation to a Small Protein on the Serum Half-Life Extension.

Conjugation of serum albumin or one of its ligands (such as fatty acid) has been an effective strategy to prolong the serum half-lives of drugs via neonatal Fc receptor (FcRn)–mediated recycling of albumin. So far, fatty acid (FA) has been effective in prolonging the serum half-lives for therapeutic peptides and small proteins, but not for large therapeutic proteins. Very recently, it was reported a large protein conjugated to FA competes with the binding of FcRn with serum albumin, leading to limited serum half-life extension, because primary FA binding sites in serum albumin partially overlap with FcRn binding sites. In order to prevent such competition, longer linkers between FA and the large proteins were required. Herein, we hypothesized that small proteins do not cause substantial competition for FcRn binding to albumin, resulting in the extended serum half-life. Using a small protein (28 kDa), we investigated whether the intramolecular distance in FA-protein conjugate affects the FcRn binding with albumin and serum half-life using linkers with varying lengths. Unlike with the FA-conjugated large protein, all FA-conjugated small proteins with different linkers exhibited comparable the FcRn binding to albumin and extended serum half-life.

Identification of Binding Sites on Human Serum Albumin for Somapacitan, a Long-Acting Growth Hormone Derivative.

Somapacitan, a human growth hormone derivative that binds reversibly to albumin, was investigated for human serum albumin (HSA) and HSA domain binding. Isothermal titration calorimetry (ITC) binding profiles showed high-affinity binding (∼100-1000 nM) of one somapacitan molecule and low-affinity binding (∼1000-10000 nM) of one to two somapacitan molecules to HSA. The high-affinity site was identified in HSA domain III using size exclusion chromatography (SEC) and ITC. SEC studies showed that the neonatal Fc receptor shields one binding site for somapacitan, indicating its position in domain III. A crystal structure of somapacitan in complex with HSA optimized for neonatal Fc receptor binding, having four amino acid residue replacements, identified a low-affinity site in fatty acid-binding site 6 (domain II). Surface plasmon resonance (SPR) showed these replacements affect the kinetics of the high-affinity binding site. Furthermore, small-angle X-ray scattering and SPR brace two somapacitan-binding sites on HSA.

Structural investigations of stereoselective profen binding by equine and leporine serum albumins.

Serum albumin, the most abundant transport protein of mammalian blood, interacts with various nonsteroidal anti-inflammatory drugs (NSAIDs) affecting their disposition, metabolism, and excretion. A big group of chiral NSAIDs transported by albumin, profens, is created by derivatives of 2-arylpropionic acid. The chiral center in the structures of profens is adjacent to the carboxylate moiety and often determines different pharmacological properties of profen enantiomers. This study describes crystal structures of two albumins, isolated from equine and leporine serum, in complexes with three profens: ibuprofen, ketoprofen, and suprofen. Based on three-dimensional structures, the stereoselectivity of albumin is discussed and referred to the previously published albumin complexes with drugs. Drug Site 2 (DS2) of albumin, the bulky hydrophobic pocket of subdomain IIIA with a patch of polar residues, preferentially binds (S)-enantiomers of all investigated profens. Almost identical binding mode of all these drugs clearly indicates the stereoselectivity of DS2 towards (S)-profens in different albumin species. Also, the affinity studies show that DS2 is the major site that presents high affinity towards investigated drugs. Additionally, crystallographic data reveal the secondary binding sites of ketoprofen in leporine serum albumin and ibuprofen in equine serum albumin, both overlapping with previously identified naproxen binding sites: the cleft formed between subdomains IIIA and IIIB close to the fatty acid binding site 5 and the niche created between subdomains IIA and IIIA, called fatty acid site 6.

Serum Albumin, Lipid and Drug Binding.

Albumin is widely conserved from vertebrates to invertebrates, and nature of mammalian albumins permit them to bind various endogenous ligands and drugs in the blood. It is known that at least two major ligand binding sites are present on the albumin molecule, which are referred to as Site I and Site II. These binding sites are thought to be almost completely conserved among mammals, even though the degree of binding to these sites are different depending on the physical and chemical properties of drugs and differences in the microenvironment in the binding pockets. In addition, the binding sites for medium and long-chain fatty acids are also well conserved among mammals, and it is considered that there are at least seven binding sites, including Site I and Site II. These bindings properties of albumin in the blood are also widely known to be important for transporting drugs and fatty acids to various tissues. It can therefore be concluded that albumin is one of the most important serum proteins for various ligands, and information on human albumin can be very useful in predicting the ligand binding properties of the albumin of other vertebrates.

Insight into the Molecular Interaction of Cloxyquin (5-chloro-8-hydroxyquinoline) with Bovine Serum Albumin: Biophysical Analysis and Computational Simulation.

Cloxyquin is a potential therapeutic compound possessing various bioactivities, especially antibacterial, antifungal, cardioprotective, and pain relief activities. Herein, the interaction mechanism between cloxyquin and bovine serum albumin (BSA) has been elucidated in order to fulfill its pharmacokinetic and pharmacodynamic gaps essential for further development as a therapeutic drug. Multi-spectroscopic and biophysical model analysis suggested that cloxyquin interacts with BSA via a static process by ground-state complex formation. Its binding behavior emerged as a biphasic fashion with a moderate binding constant at the level of 104 M−1. Thermodynamic analysis and molecular docking simulation concurrently revealed that hydrophobic interaction is a major driving force for BSA–cloxyquin complexation. Binding of cloxyquin tends to slightly enlarge the monomeric size of BSA without a significant increase of aggregate fraction. Cloxyquin preferentially binds into the fatty acid binding site 5 (FA5) of the BSA via hydrophobic interaction amongst its quinoline scaffold and Phe550, Leu531, and Leu574 residues of BSA. The quinoline ring and hydroxyl moiety of cloxyquin also form the π–π interaction and the hydrogen bond with Phe506. Our data indicate a potential function of serum albumin as a carrier of cloxyquin in blood circulation.

Fatty acid transfer between serum albumins and shungite carbon nanoparticles and its effect on protein aggregation and association.

The bioactivity of the natural ultrafine carbon form shungite nanocarbon (ShC) is of particular interest both for biomedical applications of such nanomaterials and their negative impact on the aquatic environmental. Here we studied the interaction of serum albumin (SA) with ShC nanoparticles in aqueous dispersion with respect to its structural-dynamic, thermodynamic, and hydrodynamic effects. Electron spin resonance (EPR) with a 5-DOXYL-stearic acid spin probe (5DSA) demonstrates that ShC can affect fatty acid (FA) binding by SA, protein conformation in the stearic FA spin probe binding region, and protein aggregation due to the partial transfer of FA to the ShC nanoparticles. The ratio of SA fractions changes in the presence of ShC in favor of the fraction that is less saturated with FA as shown by differential scanning calorimetry (DSC). The stability of interaction with ShC is significantly higher for aggregates of SA molecules that carry physiological amounts of FA, compared to aggregates of the FA-free protein, as studied by dynamic light scattering (DLS) analysis. Generally, the mixed dispersion of SA and ShC nanoparticles is more homogeneous than the SA solution alone. This is manifested both in the size of the molecular associates and in the microenvironment of the protein-bound FA. The formation of the SA-ShC interface is likely to result in a greater uniformity of the FA binding sites and a decrease in protein fractions and "hot patches" on the protein surface responsible for the supramolecular heterogeneity of the protein in solution.

Ruxolitinib binding to human serum albumin: bioinformatics, biochemical and functional characterization in JAK2V617F+ cell models

Ruxolitinib is a type I JAK inhibitor approved by FDA for targeted therapy of Philadelphia-negative myeloproliferative neoplasms (MPNs), all characterized by mutations activating the JAK2/STAT signaling pathway. Treatment with ruxolitinib improves constitutional symptoms and splenomegaly. However, patients can become resistant to treatment and chronic therapy has only a mild effect on molecular/pathologic remissions. Drugs interaction with plasma proteins, i.e. human serum albumin (HSA), is an important factor affecting the intensity and duration of their pharmacological actions. Here, the ruxolitinib recognition by the fatty acid binding sites (FAs) 1, 6, 7, and 9 of HSA has been investigated from the bioinformatics, biochemical and/or biological viewpoints. Docking simulations indicate that ruxolitinib binds to multiple sites of HSA. Ruxolitinib binds to the FA1 and FA7 sites of HSA with high affinity (Kr = 3.1 μM and 4.6 μM, respectively, at pH 7.3 and 37.0 °C). Moreover, HSA selectively blocks, in a dose dependent manner, the cytotoxic activity of ruxolitinib in JAK2V617F+ cellular models for MPN, in vitro. Furthermore this event is accompanied by changes in the cell cycle, p27Kip1 and cyclin D3 levels, and JAK/STAT signaling. Given the high plasma concentration of HSA, ruxolitinib trapping may be relevant in vivo.

Fatty Acid Triangulation in Albumins Using a Landmark Spin Label

AbstractSeveral spatial correlations of up to six fatty acid (FA) binding sites in albumins were found by double electron‐electron resonance (DEER). A strategy was used that combines spin‐labeling and spin‐probing techniques in electron paramagnetic resonance (EPR) spectroscopy. This is here achieved by introducing an additional covalent landmark spin (LS) label to the self‐assembled system of EPR‐active, paramagnetic stearic acid derivatives and albumins. Therefore, a cysteine specific, paramagnetic LS that was attached to the albumin surface at a unique position (Cys34) provides a fixed topological reference point for monitoring statistical ligand uptake. We propose that the determination of nanoscale distance distributions emerging between the LS and EPR‐active fatty acid derivatives generally allows for the direct observation of individually occupied binding sites in solution. Essentially, several binding pockets, groups of them and evidence for ligand‐induced allosteric modulation can be traced from such FA‐LS interspin correlations. Experimental results were substantiated with theoretical predictions from molecular dynamics (MD) simulations. It was observed that all binding sites in an albumin ensemble may be statistically filled even at the lowest level of ligand loading. This approach generally bears the potential for mapping occupation states of individual ligand binding sites in proteins using such spin‐labeled ligands.

Neonicotinoid trapping by the FA1 site of human serum albumin.

Neonicotinoids are a widely used class of insecticides that target the acetylcholine recognition site of the nicotinic acetylcholine receptors in the central nervous system of insects. Although neonicotinoids display a high specificity for insects, their use has been recently debated since several studies led to the hypothesis that they may have adverse ecological effects and potential risks to mammals and even humans. Due to their hydrophobic nature, neonicotinoids need specific carriers to allow their distribution in body fluids. Human serum albumin (HSA), the most abundant plasma protein, is a key carrier of endogenous and exogenous compounds. The in silico docking and ligand binding properties of acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam to HSA are here reported. Neonicotinoids bind to multiple fatty acid (FA) binding sites, preferentially to the FA1 pocket, with high affinity. Values of the dissociation equilibrium constant for neonicotinoid binding FA1 of HSA (i.e., calc Kn ) derived from in silico docking simulations (ranging between 3.9 × 10-5 and 6.3 × 10-4 M) agree with those determined experimentally from competitive inhibition of heme-Fe(III) binding (i.e., exp Kn ; ranging between 2.1 × 10-5 and 6.9 × 10-5 M). Accounting for the HSA concentration in vivo (~7.5 10-4 M), values of Kn here determined suggest that the formation of the HSA:neonicotinoid complexes may occur in vivo. Therefore, HSA appears to be an important determinant for neonicotinoid transport and distribution to tissues and organs, particularly to the liver where they are metabolized.

The Physicochemical Characteristics of Serum Albumin and Erythrocyte Cell Membranes under Normal and Heart Failure Symptom Conditions

Abstract—Spin labeling EPR spectroscopy was used to study the structural and conformational characteristics of human serum albumin and human erythrocyte membranes under normal conditions and with symptoms of heart failure. 5-Doxyl stearic acid and 16-doxyl stearic acid were used as spin labels, whose paramagnetic NO fragments are bound to different sites of the hydrocarbon chain. The EPR spectra of 16-doxyl stearic acid indicate that in the physiological temperature range serum albumin molecules are characterized by several types of fatty acid binding sites, which differ in parameters of spin-label rotational diffusion. This distribution of fatty-acid binding sites was typical for the blood serum of all patients who participated in our study, regardless of deviations from the normal blood parameters. The microviscosity of erythrocyte membranes from patient blood was measured using both 5-doxyl stearic and 16-doxyl stearic spin labels, whose paramagnetic fragments are located at different depths inside the lipid bilayer. It was found that in patients with an increased erythrocyte distribution width, the membrane lipid microviscosity is statistically significantly higher than under normal conditions.

Unravelling the interaction mechanism between clioquinol and bovine serum albumin by multi-spectroscopic and molecular docking approaches

Clioquinol has recently been proposed for the treatment of Alzheimer's disease. It is able to diminish β-amyloid protein aggregation and to restore cognition of Alzheimer's mice. However, its therapeutic benefits for Alzheimer's disease in human remain controversy and need further confirmation. Herein, we have explored the interaction mechanism of clioquinol toward bovine serum albumin (BSA) by means of multi-spectroscopic and docking simulation approaches. Clioquinol interacts with BSA by a combined mechanism of static and dynamic processes. Application of the Hill's equation to fluorescence quenching experiment revealed that the binding constant of the BSA-clioquinol complex is extremely high at 108 M-1 level. Competitive displacement and docking analysis consistently suggested that there are the multiple binding modes of clioquinol toward BSA. Competitive binding study showed that clioquinol shares the binding sites with ibuprofen and digitoxin on albumin, referring to be site II and site III binding compounds. Besides, partial binding in site I was also observed. Docking simulation confirmed that clioquinol favors to bind in site I, site II, site III, fatty acid binding site 5, and the protein cleft between subdomain IB and IIIB of the BSA. Due to its small size and electric dipole property, clioquinol may easily fit in multiple pockets of the BSA. Our finding suggests the potential role of BSA as a clioquinol carrier in the vascular system. Nonetheless, clioquinol-induced BSA aggregation has been observed by the three-dimensional fluorescence technique. This phenomenon may not only impair the BSA, but may also affect other endogenous proteins, which eventually causes adverse effects to human. Therefore, the redesigned or modified molecular structure of clioquinol may reduce its toxicity and improve its bioavailability.

Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling.

Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling.Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells.Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling.Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714.

Engineering of Talaromyces thermophilus lipase by altering its crevice-like binding site for highly efficient biocatalytic synthesis of chiral intermediate of Pregablin

The scissile fatty acid binding site of lipases is divided into different sub-groups and plays an important role in the catalytic properties of the enzymes. In this study, the Talaromyces thermophilus lipase was engineered by altering its crevice-like binding site for efficient synthesis of chiral intermediate of Pregablin through kinetic resolution of 2-carboxyethyl-3-cyano-5-methylhexanoic acid ethyl ester (CNDE). The substitution of residues located at the crevice-like binding site with phenylalanine (Phe) resulted in significantly increased hydrolysis activity. The variant L206F/P207F/L259F exhibited a 37.23-fold and 47.02-fold improvement in the specific activity and turnover number (kcat) toward CNDE, respectively. Simultaneously, the optimum temperature and substrate preference were both altered in the variants. The study herein successfully engineered the TTL with improved catalytic properties for efficient biosynthesis of Pregablin intermediate. The investigation of structure-functional relationship provided important guidance for further modification of lipases with crevice-like binding site domain.

Inhibition of Amyloid Aggregation of Bovine Serum Albumin by Sodium Dodecyl Sulfate at Submicellar Concentrations.

Sodium dodecyl sulfate (SDS), as an anionic surfactant, can induce protein conformational changes. Recent investigations demonstrated different effects of SDS on protein amyloid aggregation. In the present study, the effect of SDS on amyloid aggregation of bovine serum albumin (BSA) was evaluated. BSA transformed to β-sheet-rich amyloid aggregates upon incubation at pH7.4 and 65°C, as demonstrated by thioflavin T fluorescence, circular dichroism, and transmission electron microscopy. SDS at submicellar concentrations inhibited BSA amyloid aggregation with IC50 of 47.5µM. The inhibitory effects of structural analogs of SDS on amyloid aggregation of BSA were determined to explore the structure-activity relationship, with results suggesting that both anionic and alkyl moieties of SDS were critical, and that an alkyl moiety with chain length ≥10 carbon atoms was essential to amyloid inhibition. We attributed the inhibitory effect of SDS on BSA amyloid aggregation to interactions between the detergent molecule and the fatty acid binding sites on BSA. The bound SDS stabilized BSA, thereby inhibiting protein transformation to amyloid aggregates. This study reports for the first time that the inhibitory effect of SDS on albumin fibrillation is closely related to its alkyl structure. Moreover, the specific binding of SDS to albumin is the main driving force in amyloid inhibition. This study not only provides fresh insight into the role of SDS in amyloid aggregation of serum albumin, but also suggests rational design of novel anti-amyloidogenic reagents based on specific-binding ligands.

Identification and Characterization of a Single High‐Affinity Fatty Acid Binding Site in Human Serum Albumin

AbstractA single high‐affinity fatty acid binding site in the important human transport protein serum albumin (HSA) is identified and characterized using an NBD (7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)‐C12 fatty acid. This ligand exhibits a 1:1 binding stoichiometry in its HSA complex with high site‐specificity. The complex dissociation constant is determined by titration experiments as well as radioactive equilibrium dialysis. Competition experiments with the known HSA‐binding drugs warfarin and ibuprofen confirm the new binding site to be different from Sudlow‐sites I and II. These binding studies are extended to other albumin binders and fatty acid derivatives. Furthermore an X‐ray crystal structure allows locating the binding site in HSA subdomain IIA. The knowledge about this novel HSA site will be important for drug depot development and for understanding drug‐protein interaction, which are important prerequisites for modulation of drug pharmacokinetics.

Identification and Characterization of a Single High-Affinity Fatty Acid Binding Site in Human Serum Albumin.

A single high-affinity fatty acid binding site in the important human transport protein serum albumin (HSA) is identified and characterized using an NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl)-C12 fatty acid. This ligand exhibits a 1:1 binding stoichiometry in its HSA complex with high site-specificity. The complex dissociation constant is determined by titration experiments as well as radioactive equilibrium dialysis. Competition experiments with the known HSA-binding drugs warfarin and ibuprofen confirm the new binding site to be different from Sudlow-sites I and II. These binding studies are extended to other albumin binders and fatty acid derivatives. Furthermore an X-ray crystal structure allows locating the binding site in HSA subdomain IIA. The knowledge about this novel HSA site will be important for drug depot development and for understanding drug-protein interaction, which are important prerequisites for modulation of drug pharmacokinetics.

Warfarin inhibits allosterically the reductive nitrosylation of ferric human serum heme-albumin

Human serum heme-albumin (HSA-heme-Fe) displays heme-based ligand binding and (pseudo-)enzymatic properties. Here, the effect of the prototypical drug warfarin on kinetics and thermodynamics of NO binding to ferric and ferrous HSA-heme-Fe (HSA-heme-Fe(III) and HSA-heme-Fe(II), respectively) and on the NO-mediated reductive nitrosylation of the heme-Fe atom is reported; data were obtained between pH5.5 and 9.5 at 20.0°C. Since warfarin is a common drug, its effect on the reactivity of HSA-heme-Fe represents a relevant issue in the pharmacological therapy management. The inhibition of NO binding to HSA-heme-Fe(III) and HSA-heme-Fe(II) as well as of the NO-mediated reductive nitrosylation of the heme-Fe(III) atom by warfarin has been ascribed to drug binding to the fatty acid binding site 2 (FA2), shifting allosterically the penta-to-six coordination equilibrium of the heme-Fe atom toward the low reactive species showing the six-coordinated metal center by His146 and Tyr161 residues. These data: (i) support the role of HSA-heme-Fe in trapping NO, (ii) highlight the modulation of the heme-Fe-based reactivity by drugs, and (iii) could be relevant for the modulation of HSA functions by drugs in vivo.

An algal photoenzyme converts fatty acids to hydrocarbons.

Although many organisms capture or respond to sunlight, few enzymes are known to be driven by light. Among these are DNA photolyases and the photosynthetic reaction centers. Here, we show that the microalga Chlorella variabilis NC64A harbors a photoenzyme that acts in lipid metabolism. This enzyme belongs to an algae-specific clade of the glucose-methanol-choline oxidoreductase family and catalyzes the decarboxylation of free fatty acids to n-alkanes or -alkenes in response to blue light. Crystal structure of the protein reveals a fatty acid-binding site in a hydrophobic tunnel leading to the light-capturing flavin adenine dinucleotide (FAD) cofactor. The decarboxylation is initiated through electron abstraction from the fatty acid by the photoexcited FAD with a quantum yield >80%. This photoenzyme, which we name fatty acid photodecarboxylase, may be useful in light-driven, bio-based production of hydrocarbons.