FAHD1

Official Full Name

fumarylacetoacetate hydrolase domain containing 1

Organism

Homo sapiens

GeneID

81889

Background

Enables hydrolase activity, acting on acid carbon-carbon bonds, in ketonic substances; oxaloacetate decarboxylase activity; and oxaloacetate tautomerase activity. Involved in oxaloacetate metabolic process. Located in cytosol; mitochondrion; and nucleoplasm. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

ODx; YISKL; C16orf36;

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Detailed Information

Fumarylacetoacetate hydrolase domain-containing proteins (FAH) were not only found in prokaryotes but also eukaryotes. However, the association between enzymatic reactions and structural differences in their respective FAH domains has not been figured out, more detailed, the precise relationship between the structure of the FAH domain and correspond enzyme function remains to be untouchable. There are three known FAH domain-containing proteins, FAHD1, FAHD2A, and FAHD2B in mammals, and their enzymatic functions are waiting for untangled. Oxaloacetate is capable of enzymatic decarboxylation in bacteria, and molecular modeling and subsequent biochemical research revealed that FAHD1 may work as a eukaryotic ODx enzyme.

FAHD1 works as a novel regulator of mitochondrial function and senescence

A member of FAH superfamily of enzymes, FAHD1, was found to be a mitochondrial protein with differential expression in a proteomic screening initiated in young versus senescent human endothelial cells. Recent studies suggest that an important role has been played by FAHD1 in regulating mitochondrial functions for its oxaloacetate decarboxylase identity. Silence of FAHD1 gene brings human cells forward into the phase of senescence-like growth arrest by lowering down activity of the mitochondrial electron transport (ETC) system. And it may indicate that mitochondrial function is regulated by FAHD1 to lead to the consequence of senescence. To identify novel anti-senescence target, Solmaz Etemad employed unbiased proteomics approach for the identification of mitochondrial proteome, whose alteration in expression is accompanied with cellular senescence. And a previously unknown mitochondrial protein with differential distribution in young and senescent HUVEC cells, FAHD1, which was subsequently identified as a mitochondrial matrix localized eukaryotic oxaloacetate decarboxylase (ODx), was found in the comparison of the mitochondrial proteome from young and senescent human.

Fumarylacetoacetate Hydrolase Domain Containing Protein (FAHD1) inhibitors

Oxaloacetate decarboxylase role played by FAHD1 in mitochondria is beneficial for the regulation of the tricarboxylic acid cycle. The chemical structure of FAHD1 substrate oxaloacetate may foretell the potential inhibitor structures. In the account of FAHD1's role in human cell metabolism and metabolic shifts that occurred in FAHD1 knockdown human cell lines, successful experiment about assessment of cells' dependence on FAHD1 for proliferation and survival would put FAHD1 inhibition into the tract of working as a therapeutic target in treatment of pathologies associated with mitochondrial dysfunction, and translational research with this aim should be based on more text in efficacy studies in human tissue culture and xenograft models. Structural information derived from X-ray data of FAHD1 associated with comparison between unliganded with the liganded protein models enabled the definition of the FAHD1 catalytic center in high resolution.

Fig 1. Role of FAHD1 played in OAA-producing and consuming processes in mitochondrial matrix (Pidder et al. 2018)

References:

A NISHIMURA T, NAKATAKE Y, KONISHI M. (2000) 'Identification of a novel FGF, FGF-21, preferentially expressed in the liver, Biochim Biophys Acta, 2000, 1492(1): 203-206. doi: 10.1016/s0167－4781( 00) 00067－1.
Solmaz Etemad, Michèle Petit, Alexander K. H. Weiss. (2018) 'Oxaloacetate decarboxylase FAHD1 - a new regulator of mitochondrial function and senescence'. Mechanisms of Ageing, doi: 10.1016/j.mad.2018.07.007.

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