Mechanism and Substrate Recognition of Human Holo ACP Synthase

Bunkóczi, G.; Pasta, Saloni; Joshi, Anil K.; Wu, Xiaoqiu; Kavanagh, K.L.; Smith, Stuart; Oppermann, Udo

doi:10.1016/j.chembiol.2007.10.013

Cited by 81 publications

(140 citation statements)

References 37 publications

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“…All PPTs known so far are active either as trimers (bacteria) or pseudo-dimers (mammals), with the ACP bound between two PPT (pseudo-)subunits (Bunkoczi et al 2007 ;Parris et al 2000). Moreover, ACPs from both the fungal-like FASI of M. tuberculosis and the simultaneously present FAS type II system are activated by a trimeric ACP synthase (Dym et al 2009), which is encoded by an individual gene located immediately downstream of the FASI open reading frame.…”

Section: Active Sites Linkers and Substrate Shuttling In Fungal Fasmentioning

confidence: 99%

“…This enzyme is responsible for cofactor loading in all three mammalian ACP-based systems, the mitochondrial ACP as part of a bacterial type II fatty acid synthesis system, the cytosolic FAS multienzyme and the aminoadipate semialdehyde dehydrogenase. The animal holo ACP synthase most closely resembles the pseudo-dimeric Bacillus subtilis Sfp PPT regarding its domain structure, but differs with respect to the details of its catalytic mechanism and ACP recognition (Bunkoczi et al 2007).…”

Section: Domain Composition and Reaction Cyclementioning

confidence: 99%

“…The ACP domain is located downstream of the KR domain. Based on the NMR structure of the rat FAS ACP domain and the crystal structure of the human FAS ACP domain in complex with the holo ACP synthase, ACP forms a typical four-helix bundle, with the serine for cofactor attachment preceding the second helix of the bundle (Bunkoczi et al 2007 ;Ploskon et al 2008).…”

Section: Domain Composition and Reaction Cyclementioning

confidence: 99%

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Structure and function of eukaryotic fatty acid synthases

Maier

Leibundgut

Boehringer

et al. 2010

Quart. Rev. Biophys.

120

127

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Abstract. In all organisms, fatty acid synthesis is achieved in variations of a common cyclic reaction pathway by stepwise, iterative elongation of precursors with two-carbon extender units. In bacteria, all individual reaction steps are carried out by monofunctional dissociated enzymes, whereas in eukaryotes the fatty acid synthases (FASs) have evolved into large multifunctional enzymes that integrate the whole process of fatty acid synthesis. During the last few years, important advances in understanding the structural and functional organization of eukaryotic FASs have been made through a combination of biochemical, electron microscopic and X-ray crystallographic approaches. They have revealed the strikingly different architectures of the two distinct types of eukaryotic FASs, the fungal and the animal enzyme system. Fungal FAS is a 2Á6 MDa a 6 b 6 heterododecamer with a barrel shape enclosing two large chambers, each containing three sets of active sites separated by a central wheel-like structure. It represents a highly specialized micro-compartment strictly optimized for the production of saturated fatty acids. In contrast, the animal FAS is a 540 kDa X-shaped homodimer with two lateral reaction clefts characterized by a modular domain architecture and large extent of conformational flexibility that appears to contribute to catalytic efficiency.

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Section: Active Sites Linkers and Substrate Shuttling In Fungal Fasmentioning

confidence: 99%

Section: Domain Composition and Reaction Cyclementioning

confidence: 99%

Section: Domain Composition and Reaction Cyclementioning

confidence: 99%

See 1 more Smart Citation

Structure and function of eukaryotic fatty acid synthases

Maier

Leibundgut

Boehringer

et al. 2010

Quart. Rev. Biophys.

120

127

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“…So far, only one PPT gene has been identified in the human genome. It encodes a 329-residue monomeric enzyme that exhibits broad substrate specificity (25). This cytosolic enzyme is capable of modifying the ACP domain of FAS and mitochondrial ACP (20) and has been also implicated in the modification of ␣-aminoadipate semialdehyde dehydrogenase (21).…”

mentioning

confidence: 99%

Acyl Carrier Protein-specific 4′-Phosphopantetheinyl Transferase Activates 10-Formyltetrahydrofolate Dehydrogenase

Strickland

Hoeferlin

Oleinik

et al. 2010

Journal of Biological Chemistry

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4-Phosphopantetheinyl transferases (PPTs) catalyze the transfer of 4-phosphopantetheine (4-PP) from coenzyme A to a conserved serine residue of their protein substrates. In humans, the number of pathways utilizing the 4-PP posttranslational modification is limited and may only require a single broad specificity PPT for all phosphopantetheinylation reactions. Recently, we have shown that one of the enzymes of folate metabolism, 10-formyltetrahydrofolate dehydrogenase (FDH), requires a 4-PP prosthetic group for catalysis. This moiety acts as a swinging arm to couple the activities of the two catalytic domains of FDH and allows the conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO 2 . In the current study, we demonstrate that the broad specificity human PPT converts apo-FDH to holoenzyme and thus activates FDH catalysis. Silencing PPT by small interfering RNA in A549 cells prevents FDH modification, indicating the lack of alternative enzymes capable of accomplishing this transferase reaction. Interestingly, PPT-silenced cells demonstrate significantly reduced proliferation and undergo strong G 1 arrest, suggesting that the enzymatic function of PPT is essential and nonredundant. Our study identifies human PPT as the FDH-modifying enzyme and supports the hypothesis that mammals utilize a single enzyme for all phosphopantetheinylation reactions.Folate derivatives function as coenzymes in reactions involving the transfer of one-carbon units and participate in key metabolic processes, including nucleotide biosynthesis and the regeneration of methionine from homocysteine (1). The intracellular folate pool consists of several major reduced folate forms, and the overall balance between different folates is maintained by numerous enzymes that incorporate one-carbon groups into the pool, convert these groups within the pool, or utilize them in biosynthetic reactions. One of the folate enzymes, 10-formyltetrahydrofolate (10-fTHF) 2 dehydrogenase (FDH, aldehyde dehydrogenase 1L1, EC 1.5.1.6), oxidizes the formyl group of 10-fTHF to yield tetrahydrofolate (THF) and CO 2 . This reaction requires NADP ϩ and proceeds through a complex multistep mechanism (2). FDH is expressed in most tissues and is particularly abundant in the liver and kidney; in the former it is present at the level of about 1% of the total soluble cytosolic protein (3).The FDH substrate, 10-fTHF, is used as a formyl group donor in two steps of de novo purine biosynthesis (4, 5). The excess of 10-fTHF, not required for this pathway, can be utilized by FDH to replenish the THF pool, thus making folate available for other reactions of one-carbon metabolism. It has been proposed that the FDH reaction serves as a regulator of intracellular purine levels, preventing the excessive flux of one-carbon groups into this pathway (6). Several other metabolic functions have also been attributed to FDH, including storage of intracellular folate in the form of THF (7); detoxification of intracellular formic acid by removing it as CO 2 (8); and regulation of o...

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“…[180][181] Grupos de pesquisa têm desenvolvido e implementado plataforma de clonagem e expressão em larga escala, na qual a seleção de alvos viáveis utiliza dados como triagem de expressão, rendimento e atividade da proteína de interesse. [182][183][184][185][186][187] …”

Section: Motivação Científicaunclassified

Estudos estruturais de enzimas da via de biossíntese de folatos de <i>Xanthomonas albilineans</i> para o desenvolvimento de novos candidatos a agroquímicos para a cultura de cana-de-açúcar

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Mechanism and Substrate Recognition of Human Holo ACP Synthase

Cited by 81 publications

References 37 publications

Structure and function of eukaryotic fatty acid synthases

Structure and function of eukaryotic fatty acid synthases

Acyl Carrier Protein-specific 4′-Phosphopantetheinyl Transferase Activates 10-Formyltetrahydrofolate Dehydrogenase

Estudos estruturais de enzimas da via de biossíntese de folatos de <i>Xanthomonas albilineans</i> para o desenvolvimento de novos candidatos a agroquímicos para a cultura de cana-de-açúcar

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