Identification of Human Fumarylacetoacetate Hydrolase Domain-containing Protein 1 (FAHD1) as a Novel Mitochondrial Acylpyruvase

Pircher, Haymo; Straganz, Grit Daniela; Ehehalt, Daniela; Morrow, Geneviève; Tanguay, Robert M.; Jansen‐Dürr, Pidder

doi:10.1074/jbc.m111.264770

Cited by 33 publications

(45 citation statements)

References 16 publications

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“…Interestingly, the enzyme kinetics of FAHD1 closely resemble some of the values reported for an unidentified mammalian ODx in earlier years [4,3]. The mutation of key residues located within the catalytic domain, including a catalytic loop, resulted in abrogated or reduced enzymatic activity.As already observed in an earlier study [8], FAHD1 is located in mitochondria, showing highest expression in kidney and liver. Oxaloacetate levels in the kidneys and livers of FAHD1-/-mice were significantly increased in comparison to their wildtype littermates, thereby providing evidence for the in vivo relevance of FAHD1's ODx activity.…”

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confidence: 59%

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The FAH Fold Meets the Krebs Cycle

Jansen-Duerr¹,

Pircher²,

Weiss³

2016

Mol Enzyme Drug Targ

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EditorialThe Krebs (or tricarboxylic acid, TCA) cycle forms a central junction in aerobic metabolism, being connectedto glycolysis, gluconeogenesis, fatty acid metabolism and amino acid metabolism ( Figure 1). Pyruvate carboxylase (PC) catalyzes the carboxylation of pyruvate to form oxaloacetate, an important so-called anaplerotic reaction to provide a sufficient level of metabolites for the TCA cycle. The breakdown of oxaloacetate to pyruvate by oxaloacetate decarboxylases (ODx) is mainly known from prokaryotic organisms where two main variants of ODx enzymes are known: a membrane-bound variant that depends on sodium and biotin [1] and a soluble variant that depends on divalent cations [2]. Far less is known about ODx activity in mammalian organisms, apart from the promiscuous activity of some metabolic enzymes [3].Many decades ago several reports about an ODx enzyme purified from extracts of rat liver mitochondria surfaced [4,3], but curiously enough the identity of such an enzyme was never clarified.Until recently, members of the FAH family of enzymes were not known to be connected to the TCA cycle in any way. The eponymous FAH enzyme acts as a fumarylacetoacetate hydrolase, catalyzing the final step of the tyrosine breakdown [5]. Loss of this function causes hereditary tyrosinemia type I (HTI) in humans [6].The prokaryotic realm provides a perplexingly large number of FAH type enzymes which, in spite of the structural similarity of their catalytic domains, collectively referred to as the FAH fold, catalyze a wide range of reactions [7]. They comprise hydrolases, isomerases, decarboxylases, hydratases and dehydratases, demonstrating the versatility of the FAH fold. Besides FAH itself, the only other members of the FAH superfamily present in mammalian organisms are FAHD1 (fumarylacetoacetate hydrolase domain containing protein 1) and FAHD2. Classification of their function has proven difficult due to the aforementioned spectrum of FAH fold activities. In a first study, the comparison of FAHD1's primary sequence with prokaryotic members of the FAH family led to the observation that FAHD1 exhibits acylpyruvate hydrolaseThis activity is so far not associated with mammalian metabolism, however. In a recent study to further investigate the cellular role of FAHD1, molecular modeling was applied to search for a close structural match between the catalytic domain of FAHD1 and other members of the FAH family [9]. This process yielded the prokaryotic enzyme Cg1458 as a promising candidate, previously identified as a soluble ODx [2].Subsequent in vitro analysis of purified recombinant human FAHD1 confirmed that it indeed exhibits ODx activity. Interestingly, the enzyme kinetics of FAHD1 closely resemble some of the values reported for an unidentified mammalian ODx in earlier years [4,3]. The mutation of key residues located within the catalytic domain, including a catalytic loop, resulted in abrogated or reduced enzymatic activity.As already observed in an earlier study [8], FAHD1 is located in mitochondria, showing high...

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supporting

confidence: 59%

“…Classification of their function has proven difficult due to the aforementioned spectrum of FAH fold activities. In a first study, the comparison of FAHD1's primary sequence with prokaryotic members of the FAH family led to the observation that FAHD1 exhibits acylpyruvate hydrolase activity [8].…”

mentioning

confidence: 99%

The FAH Fold Meets the Krebs Cycle

Jansen-Duerr¹,

Pircher²,

Weiss³

2016

Mol Enzyme Drug Targ

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“…Expression and Evidence for in Vivo Activity in Mice-Previous studies, using a polyclonal antiserum raised against recombinant FAHD1 protein, indicated a widespread expression pattern for FAHD1 in many mouse tissues, based on two distinct bands revealed by Western blot (10). In view of the specific ODx activity for FAHD1 revealed here, the expression pattern of FAHD1 was reinvestigated by improved immunological reagents.…”

Section: Journal Of Biological Chemistry 6759mentioning

confidence: 99%

“…Bacterial Recombinant Expression and Purification of FAHD1-N-terminally His-and S-tagged versions of human wild-type FAHD1 and three mutants (H30A, E33A, and D102A/R106A) were recombinantly expressed in E. coli and purified as reported previously (10).…”

Section: Structural Investigation Of the Fah Domain Active Sites-mentioning

confidence: 99%

“…In the case of acetylpyruvate, V max was determined as 0.14 mol min Ϫ1 mg Ϫ1 , with a K m value of 4.6 M. The reaction rate was found to be dependent on the type of the bound divalent metal ion, with Mg 2ϩ and Mn 2ϩ yielding the highest rates. Immunoblot analysis indicated widespread expression of FAHD1 in various murine tissues, with highest expression in kidney and liver, as well as in a wide range of human cell lines; immunofluorescence studies showed clear mitochondrial localization (10).…”

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Identification of FAH Domain-containing Protein 1 (FAHD1) as Oxaloacetate Decarboxylase

Pircher¹,

Grafenstein²,

Diener³

et al. 2015

Journal of Biological Chemistry

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Background: Enzymes of the FAH superfamily catalyze a multitude of diverse chemical reactions. Results: Using molecular modeling followed by biochemical investigations, FAHD1 was identified as oxaloacetate decarboxylase. Conclusion: Our findings suggest that ODx activity can be found in eukaryotic members of the FAH superfamily. Significance: Our results identify a mammalian ODx enzyme as a so far undescribed player in mitochondrial metabolism.

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Investigation of Glycosylphosphatidylinositol (GPI)‐Plasma Membrane Interaction in Live Cells and the Influence of GPI Glycan Structure on the Interaction

Kundu,

Jaiswal,

Babu Mullapudi

et al. 2023

Chemistry A European J

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Glycosylphosphatidylinositols (GPIs) need to interact with other components in the cell membrane to transduce transmembrane signals. A bifunctional GPI probe was employed for photoaffinity‐based proximity labelling and identification of GPI‐interacting proteins in the cell membrane. This probe contained the entire core structure of GPIs and was functionalized with photoreactive diazirine and clickable alkyne to facilitate its crosslinking with proteins and attachment of an affinity tag. It was disclosed that this probe was more selective than our previously reported probe containing only a part structure of the GPI core for cell membrane incorporation and an improved probe for studying GPI‐cell membrane interaction. Eighty‐eight unique membrane proteins, many of which are related to GPIs/GPI‐anchored proteins, were identified utilizing this probe. The proteomics dataset is a valuable resource for further analyses and data mining to find new GPI‐related proteins and signalling pathways. A comparison of these results with those of our previous probe provided direct evidence for the profound impact of GPI glycan structure on its interaction with the cell membrane.

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Identification of Human Fumarylacetoacetate Hydrolase Domain-containing Protein 1 (FAHD1) as a Novel Mitochondrial Acylpyruvase

Cited by 33 publications

References 16 publications

The FAH Fold Meets the Krebs Cycle

The FAH Fold Meets the Krebs Cycle

Identification of FAH Domain-containing Protein 1 (FAHD1) as Oxaloacetate Decarboxylase

Investigation of Glycosylphosphatidylinositol (GPI)‐Plasma Membrane Interaction in Live Cells and the Influence of GPI Glycan Structure on the Interaction

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