Mechanism of fatty acid desaturation: a bioorganic perspective

Behrouzian, Behnaz; Buist, Peter H.

doi:10.1016/s0952-3278(02)00260-0

Cited by 50 publications

(42 citation statements)

References 35 publications

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“…Fatty acid desaturases are part of multicomponent systems that catalyze the oxygen-and nicotinamide adenine dinucleotidedependent syn-dehydrogenation of unactivated aliphatic regions of their fatty ester (acyl-lipid) or thioester (acyl-acyl carrier protein or acyl-CoA) substrates (1)(2)(3)(4)(5)(6). In addition to the family of soluble fatty acid desaturases, of which the plant stearoyl-acyl carrier protein desaturase is well characterized, there is a large group of structurally distinct integral membrane desaturases.…”

mentioning

confidence: 99%

Domain Swapping Localizes the Structural Determinants of Regioselectivity in Membrane-bound Fatty Acid Desaturases of Caenorhabditis elegans

Sasata

Reed

Loewen

et al. 2004

Journal of Biological Chemistry

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Most fatty acid desaturases are members of a large superfamily of integral membrane, O 2 -dependent, ironcontaining enzymes that catalyze a variety of oxidative modifications to lipids. Sharing a similar primary structure and membrane topology, these enzymes are broadly categorized according to their positional specificity or regioselectivity, which designates the preferred position for substrate modification. To investigate the structural basis of regioselectivity in membrane-bound desaturases, the Caenorhabditis elegans -3 (FAT-1) and "⌬12" (FAT-2) desaturases were used as a model system. With the use of unnatural substrates, the regioselectivity of C. elegans FAT-2 was clearly defined as ؉3, i.e. it "measures" three carbons from an existing double bond. The structural basis for ؉3 and -3 regioselectivities was examined through construction and expression of chimeric DNA sequences based on FAT-1 and FAT-2. Each sequence was divided into seven domains, and chimeras were constructed in which specific domains were replaced with sequence from the other desaturase. When tested by expression in yeast using exogenously supplied substrates, chimeric sequences were found in which domain swapping resulted in a change of regioselectivity from ؉3 to -3 and vice versa. In this way, the structural determinants of regioselectivity in FAT-1 and FAT-2 have been localized to two interdependent regions: a relatively hydrophobic region between the first two histidine boxes and the carboxyl-terminal region.Fatty acid desaturases are part of multicomponent systems that catalyze the oxygen-and nicotinamide adenine dinucleotidedependent syn-dehydrogenation of unactivated aliphatic regions of their fatty ester (acyl-lipid) or thioester (acyl-acyl carrier protein or acyl-CoA) substrates (1-6). In addition to the family of soluble fatty acid desaturases, of which the plant stearoyl-acyl carrier protein desaturase is well characterized, there is a large group of structurally distinct integral membrane desaturases. Membrane desaturases of widely varying substrate specificity and regioselectivity are scattered among a range of taxa. The yeast Saccharomyces cerevisiae has a single stearoyl-CoA ⌬9 desaturase, whereas many bacteria lack such desaturases entirely. At the other extreme, the biosynthesis of (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoic acid in some marine fungi likely requires the successive action of six structurally similar membrane desaturases, each varying in substrate specificity and regioselectivity (7,8).Based on structural and catalytic similarities, membrane desaturases are included in a superfamily of oxidative enzymes along with alkane hydroxylase, xylene monooxygenase, carotene ketolase, and sterol methyloxidase (9, 10). These are thought to contain a histidine-coordinated diiron center at the active site. While essentially no three-dimensional structural information is available for these difficult to purify enzymes, primary structure similarity, especially the conservation of three histidine-rich motifs, and similarity o...

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confidence: 99%

Domain Swapping Localizes the Structural Determinants of Regioselectivity in Membrane-bound Fatty Acid Desaturases of Caenorhabditis elegans

Sasata

Reed

Loewen

et al. 2004

Journal of Biological Chemistry

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“…Desaturation is an aerobic process utilizing molecular oxygen and reducing equivalents obtained from an electron transport chain (15,16). The electron donor depends only on the subcellular location of the desaturase, being cytochrome b5 in endoplasmic reticulum and ferredoxin in plastids and bacteria.…”

Section: Aerobic Pathwaymentioning

confidence: 99%

“…Exceptions to this rule are the AA desaturase from Saprolegnia diclina (22), the o3 desaturase from Mortierella alpina (23) and FAT1 from Caenorhabditis elegans (24). Mammalian cells lack methyl-end desaturases, so they are absolutely dependent on the essential fatty acids linoleic acid (LA, 18:2D 9,12 ) and a-linolenic acid (ALA, 18:3D 9,12,15 ) taken from the diet as precursors for PUFA biosynthesis.…”

Section: Aerobic Pathwaymentioning

confidence: 99%

“…Although the elongases and D6 and D5 desaturases have already been isolated from mammals and functionally characterized, there is no evidence for the presence of a D4 desaturase. Sprecher and co-workers have proposed an alternative way (25), which involves the consecutive elongation of EPA to 22:5 and then to 24:5D 9,12,15,18,21 , the desaturation by D6 desaturase to 24:6D 6,9,12,15,18,21 , all in endoplasmic reticulum, and a retroconversion to DHA by b-oxidation in peroxisomes. After 15 years, enough evidence has accumulated to support the presence of the Sprecher pathway, which appears to be restricted to mammals.…”

Section: Aerobic Pathwaymentioning

confidence: 99%

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Biosynthesis of polyunsaturated fatty acids in lower eukaryotes

Uttaro

2006

IUBMB Life

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SummaryPolyunsaturated fatty acids have important structural roles in cell membranes. They are also intermediates in the synthesis of biologically active molecules such as eicosanoids, which mediate fever, inflammation, blood pressure and neurotransmission. Arachidonic and docosahexaenoic acids are essential components of brain tissues and, through their involvement in the development of neural and retinal functions, important dietary nutrients for neonatal babies. Lower eukaryotes are particularly rich in C20-22 polyunsaturated fatty acids. Fungi and marine microalgae are currently used to produce nutraceutic oils. Other protists and algae are being studied because of the variability in their enzymes involved in polyunsaturated fatty acid biosynthesis. Such enzymes could be used as source for the production of transgenic organisms able to synthesize designed oils for human diet or, in the case of parasitic protozoa, they might be identified as putative chemotherapeutic targets. Polyunsaturated fatty acids can be synthesized by two different pathways: an anaerobic one, by using polyketide synthase related enzymes, and an aerobic one, which involves the action of elongases and oxygen dependent desaturases. Desaturases can be classified into three main types, depending on which of the consecutive steps of polyunsaturated fatty acid synthesis they are involved with. The enzymes may be specialized to act on: saturated substrates (type I); mono-and di-unsaturated fatty acids by introducing additional double bonds at the methyl-end site of the existing double bonds (type II); or the carboxy half ('front-end') of polyunsaturated ones (type III). Type III desaturases require the alternating action of elongases. A description of the enzymes that have been isolated and functionally characterized is provided, in order to highlight the different pathways found in lower eukaryotes.

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“…However, the studies on corresponding enzymes are extremely difficult since the desaturases are membrane-bound proteins. [39] In order to probe the active site of the soluble plant Δ 9 -desaturases, Buist et al have prepared and submitted to biological tests various fluorinated analogues of its natural substrate (stearic acid). Among these derivatives, the 9-fluorostearate 137 has been synthesized in racemic form by a classical route, as indicated in Scheme 23.…”

Section: Natural Fluorinated Fatty Acids and Biosynthetic Studiesmentioning

confidence: 99%

Synthesis of Fluoro Analogues of Unsaturated Fatty Acids and Corresponding Acyclic Metabolites

et al. 2005

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Polyunsaturated fatty acids, in particular arachidonic acid and its metabolites, the so‐called eicosanoids, play a major role in human health. Many of them have been involved as potent mediators for various diseases such as inflammation and asthma. Therefore, numerous modifications in the structures of these natural products have been incorporated to study the structure‐activity relationship, monitor the biosynthetic pathway and also to understand the biological activities as well as the mechanisms of action. The modifications include introduction of labelled elements, fluorine atoms, heteroelements, carbo‐ and heterocycles etc. Of all these studies, the introduction of fluorine, which has a unique role as the smallest atom in the periodic table after hydrogen and also as the most electronegative element, provided very useful information. Thus, the present microreview highlights the synthetic efforts of various research groups in the last two decades on bioactive fluorinated fatty acids and corresponding acyclic metabolites. It also presents the most relevant bioactivity data obtained from the fluorinated analogues. The data corresponding to naturally occurring fluorinated fatty acids have been added, as well as the use of fluorinated probes for some biosynthetic studies in fatty acid chemistry (desaturation and methylenation). In addition, it is important to point out that the methods and strategies which have been developed to selectively introduce a single fluorine atom, as well as CF2 or CF3 groups, on such very challenging molecules could also be of much use in many other areas of chemistry. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

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Mechanism of fatty acid desaturation: a bioorganic perspective

Cited by 50 publications

References 35 publications

Domain Swapping Localizes the Structural Determinants of Regioselectivity in Membrane-bound Fatty Acid Desaturases of Caenorhabditis elegans

Domain Swapping Localizes the Structural Determinants of Regioselectivity in Membrane-bound Fatty Acid Desaturases of Caenorhabditis elegans

Biosynthesis of polyunsaturated fatty acids in lower eukaryotes

Synthesis of Fluoro Analogues of Unsaturated Fatty Acids and Corresponding Acyclic Metabolites

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