Analysis of proteins with the 'hot dog' fold: Prediction of function and identification of catalytic residues of hypothetical proteins

Pidugu, Lakshmi S; Maity, Koustav; Ramaswamy, Karthikeyan; Surolia, Namita; Suguna, K.

doi:10.1186/1472-6807-9-37

Cited by 51 publications

(86 citation statements)

References 47 publications

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“…In fact, ECH2 is more similar (;51% identical) to the enoyl-CoA hydratase domain from metazoan MULTIFUNCTIONAL ENZYME (MFE2) than it is the enoyl-CoA hydratase domains from IBR10 (11% identical) or plant multifunctional enzymes such as AIM1 (;8% identical) ( Figure 1D). Unlike IBR10 and the plant multifunctional enzymes, members of the ECH2 family and the metazoan MFE2 family contain hot dog domains (see Supplemental Figure 5 online), a motif associated with both enoyl-CoA hydratases and thioesterases (Pidugu et al, 2009). ECH2 has bidirectional enoylCoA hydratase activity when heterologously expressed in Saccharomyces cerevisiae (Goepfert et al, 2006).…”

Section: Discussion Peroxisomal Enzymes Implicated In Iba-to-iaa Convmentioning

confidence: 99%

“…demonstration that overexpression of one cannot compensate for loss of the other (Figure 3) suggests that ECH2 and IBR10 catalyze different reactions. Given the mechanistic and sequence similarity between hydrolases and hydratases (Pidugu et al, 2009), it is tempting to speculate that one produces the IBA hydroxylacyl-CoA thioester intermediate and the other hydrolyzes IAA-CoA to release free IAA. Resolution of this question awaits the availability of postulated substrates needed for the biochemical characterization of these enzymes.…”

Section: Discussion Peroxisomal Enzymes Implicated In Iba-to-iaa Convmentioning

confidence: 99%

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Multiple Facets ofArabidopsisSeedling Development Require  Indole-3-Butyric Acid–Derived Auxin

et al. 2011

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Levels of auxin, which regulates both cell division and cell elongation in plant development, are controlled by synthesis, inactivation, transport, and the use of storage forms. However, the specific contributions of various inputs to the active auxin pool are not well understood. One auxin precursor is indole-3-butyric acid (IBA), which undergoes peroxisomal b-oxidation to release free indole-3-acetic acid (IAA). We identified ENOYL-COA HYDRATASE2 (ECH2) as an enzyme required for IBA response. Combining the ech2 mutant with previously identified iba response mutants resulted in enhanced IBA resistance, diverse auxin-related developmental defects, decreased auxin-responsive reporter activity in both untreated and auxin-treated seedlings, and decreased free IAA levels. The decreased auxin levels and responsiveness, along with the associated developmental defects, uncover previously unappreciated roles for IBA-derived IAA during seedling development, establish IBA as an important auxin precursor, and suggest that IBA-to-IAA conversion contributes to the positive feedback that maintains root auxin levels.

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Section: Discussion Peroxisomal Enzymes Implicated In Iba-to-iaa Convmentioning

confidence: 99%

Section: Discussion Peroxisomal Enzymes Implicated In Iba-to-iaa Convmentioning

confidence: 99%

Multiple Facets ofArabidopsisSeedling Development Require  Indole-3-Butyric Acid–Derived Auxin

et al. 2011

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“…. .D motif that was reported earlier to be an important consensus sequence motif in bacterial and mammalian Hotdog thioesterases (26). Both ⌬36Them4 and ⌬34Them5 crystal structures have two active sites per homodimer, located at the end of each Hotdog helix, with residues from both subunits contributing to catalysis.…”

Section: Them5 Is a Mitochondrial Protein Bioinformatic Analysis Ofmentioning

confidence: 99%

“…S2D in the supplemental material). These residues are proposed to bind and hydrolyze the thioester moiety of the acyl-CoA substrate, as described for a number of other Hotdog thioesterases (8,26). They are located in the middle of a long L-shaped channel that is limited in length by a stretch of residues from the N-terminal part (residues 74 to 79 in ⌬36Them4 and residues 83 to 88 in ⌬34Them5), which likely defines the length of the CoA-coupled fatty acids accepted for turnover.…”

Section: Them5 Is a Mitochondrial Protein Bioinformatic Analysis Ofmentioning

confidence: 99%

“…These are cytoplasmic Acot7 involved in eicosanoid metabolism, Acot11 and Acot12, which have a START domain, and cytoplasmic/mitochondrial Them2, which is induced by peroxisome proliferator-activated receptor ␣ (PPAR␣) and has been recently shown to regulate hepatic metabolism (5,8,16,18). The mammalian Hotdog thioesterases identified thus far have tetrameric or hexameric arrangements (26).…”

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confidence: 99%

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Acyl Coenzyme A Thioesterase Them5/Acot15 Is Involved in Cardiolipin Remodeling and Fatty Liver Development

Zhuravleva

Gut

Hynx

et al. 2012

Molecular and Cellular Biology

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f Acyl coenzyme A (acyl-CoA) thioesterases hydrolyze thioester bonds in acyl-CoA metabolites. The majority of mammalian thioesterases are ␣/␤-hydrolases and have been studied extensively. A second class of Hotdog-fold enzymes has been less well described. Here, we present a structural and functional analysis of a new mammalian mitochondrial thioesterase, Them5. Them5 and its paralog, Them4, adopt the classical Hotdog-fold structure and form homodimers in crystals. In vitro, Them5 shows strong thioesterase activity with long-chain acyl-CoAs. Loss of Them5 specifically alters the remodeling process of the mitochondrial phospholipid cardiolipin. Them5 ؊/؊ mice show deregulation of lipid metabolism and the development of fatty liver, exacerbated by a high-fat diet. Consequently, mitochondrial morphology is affected, and functions such as respiration and ␤-oxidation are impaired. The novel mitochondrial acyl-CoA thioesterase Them5 has a critical and specific role in the cardiolipin remodeling process, connecting it to the development of fatty liver and related conditions. T hioesterases participate in lipid metabolism by hydrolyzing thioester bonds in a variety of substrates, including fatty acidcoenzyme A (CoA) esters and palmitoylated proteins (17,19). Based on structural folds and the catalytic reaction mechanism, thioesterases are subdivided into ␣/␤-hydrolases and Hotdogfold thioesterases. The majority of mammalian thioesterases are the well-studied ␣/␤-hydrolases; the second class of Hotdog-fold enzymes has been described to a lesser extent (19). Of the eight Hotdog-fold proteins identified thus far in mammals, only a few participate in biological processes involving hydrolysis of acylCoAs (5). These are cytoplasmic Acot7 involved in eicosanoid metabolism, Acot11 and Acot12, which have a START domain, and cytoplasmic/mitochondrial Them2, which is induced by peroxisome proliferator-activated receptor ␣ (PPAR␣) and has been recently shown to regulate hepatic metabolism (5,8,16,18). The mammalian Hotdog thioesterases identified thus far have tetrameric or hexameric arrangements (26).Them5 is part of the mitochondrial proteome and is predicted to be a member of the Hotdog-fold family (5, 24). We show here that Them5, a novel thioesterase with strong specificity for long and unsaturated fatty acid-CoA esters, has the classical Hotdogfold with six ␤-sheets wrapped around a central ␣-helix. Them4 and Them5 form independent homodimers in crystals, suggesting that they represent a new group of mammalian hotdog thioesterases.Them5 Ϫ/Ϫ mice exhibit an increase in monolysocardiolipin, one of the specific metabolites of cardiolipin (CL). CL is a mitochondrion-specific phospholipid characterized by three to four linoleic acid chains (C 18:2 ) in its mature forms, particularly in mammals. Proper synthesis and remodeling (i.e., maintenance of the right acyl composition) of these highly unsaturated CL molecules is crucial for mitochondrial physiology, since CL interacts with many mitochondrial proteins. In the Barth syndrome, a...

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Fatty Acyl Synthetases and Thioesterases in Plant Lipid Metabolism: Diverse Functions and Biotechnological Applications

Kalinger

Pulsifer

Hepworth

et al. 2020

Lipids

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Plants use fatty acids to synthesize acyl lipids for many different cellular, physiological, and defensive roles. These roles include the synthesis of essential membrane, storage, or surface lipids, as well as the production of various fatty acid-derived metabolites used for signaling or defense. Fatty acids are activated for metabolic processing via a thioester linkage to either coenzyme A or acyl carrier protein. Acyl synthetases metabolically activate fatty acids to their thioester forms, and acyl thioesterases deactivate fatty acyl thioesters to free fatty acids by hydrolysis. These two enzyme classes therefore play critical roles in lipid metabolism. This review highlights the surprisingly complex and varying roles of fatty acyl synthetases in plant lipid metabolism, including roles in the intracellular trafficking of fatty acids. This review also surveys the many specialized fatty acyl thioesterases characterized to date in plants, which produce a great diversity of fatty acid products in a tissue-specific manner. While some acyl thioesterases produce fatty acids that clearly play roles in plant-insect or plant-microbial interactions, most plant acyl thioesterases have yet to be fully characterized both in terms of their substrate specificities and their functions. The biotechnological applications of plant acyl thioesterases and synthetases are also discussed, as there is significant interest in these enzymes as catalysts for the sustainable production of fatty acids and their derivatives for industrial uses.

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Analysis of proteins with the 'hot dog' fold: Prediction of function and identification of catalytic residues of hypothetical proteins

Cited by 51 publications

References 47 publications

Multiple Facets ofArabidopsisSeedling Development Require  Indole-3-Butyric Acid–Derived Auxin

Multiple Facets ofArabidopsisSeedling Development Require  Indole-3-Butyric Acid–Derived Auxin

Acyl Coenzyme A Thioesterase Them5/Acot15 Is Involved in Cardiolipin Remodeling and Fatty Liver Development

Fatty Acyl Synthetases and Thioesterases in Plant Lipid Metabolism: Diverse Functions and Biotechnological Applications

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Analysis of proteins with the 'hot dog' fold: Prediction of function and identification of catalytic residues of hypothetical proteins

Cited by 51 publications

References 47 publications

Multiple Facets ofArabidopsisSeedling Development Require &#x2028;Indole-3-Butyric Acid–Derived Auxin

Multiple Facets ofArabidopsisSeedling Development Require &#x2028;Indole-3-Butyric Acid–Derived Auxin

Acyl Coenzyme A Thioesterase Them5/Acot15 Is Involved in Cardiolipin Remodeling and Fatty Liver Development

Fatty Acyl Synthetases and Thioesterases in Plant Lipid Metabolism: Diverse Functions and Biotechnological Applications

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Multiple Facets ofArabidopsisSeedling Development Require  Indole-3-Butyric Acid–Derived Auxin

Multiple Facets ofArabidopsisSeedling Development Require  Indole-3-Butyric Acid–Derived Auxin