A Fungal Perspective on Human Inborn Errors of Metabolism: Alkaptonuria and Beyond

Peñalva, Miguel

doi:10.1006/fgbi.2001.1284

Cited by 21 publications

(14 citation statements)

References 26 publications

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“…Intriguingly, whereas the two genes form a divergently oriented DNGP in several fungi (Fig. 1A), they do not show the same organization in the human genome (21). These results argue that amelioration of the deleterious effects of toxic ICs is a metabolic phenotype favored by selection in fungi as well as more generally across eukaryotes, resulting in DNGP formation.…”

Section: Phytophthora Infestansmentioning

confidence: 93%

“…The human metabolic disease tyrosinemia also exists in multiple types that differ in severity, which are mimicked by the phenotypes of the corresponding gene knockouts in the model fungus Aspergillus nidulans (21). Tyrosinemia type I, the most severe, results from the loss of the final step in the pathway and the accumulation of the reactive, genotoxic compound fumarylacetoacetate, which increases the incidence of hepatic cancer (21). Similar to the Gal pathway, the genes of this metabolic pathway are also clustered in many fungal species, including A. nidulans (21) (Fig.…”

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confidence: 99%

“…Tyrosinemia type I, the most severe, results from the loss of the final step in the pathway and the accumulation of the reactive, genotoxic compound fumarylacetoacetate, which increases the incidence of hepatic cancer (21). Similar to the Gal pathway, the genes of this metabolic pathway are also clustered in many fungal species, including A. nidulans (21) (Fig. 1B).…”

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confidence: 99%

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Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

McGary

Slot

Rokas

2013

Proc. Natl. Acad. Sci. U.S.A.

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Genomic analyses have proliferated without being tied to tangible phenotypes. For example, although coordination of both gene expression and genetic linkage have been offered as genetic mechanisms for the frequently observed clustering of genes participating in fungal metabolic pathways, elucidation of the phenotype(s) favored by selection, resulting in cluster formation and maintenance, has not been forthcoming. We noted that the cause of certain well-studied human metabolic disorders is the accumulation of toxic intermediate compounds (ICs), which occurs when the product of an enzyme is not used as a substrate by a downstream neighbor in the metabolic network. This raises the hypothesis that the phenotype favored by selection to drive gene clustering is the mitigation of IC toxicity. To test this, we examined 100 diverse fungal genomes for the simplest type of cluster, gene pairs that are both metabolic neighbors and chromosomal neighbors immediately adjacent to each other, which we refer to as "double neighbor gene pairs" (DNGPs). Examination of the toxicity of their corresponding ICs shows that, compared with chromosomally nonadjacent metabolic neighbors, DNGPs are enriched for ICs that have acutely toxic LD 50 doses or reactive functional groups. Furthermore, DNGPs are significantly more likely to be divergently oriented on the chromosome; remarkably, ∼40% of these DNGPs have ICs known to be toxic. We submit that the structure of synteny in metabolic pathways of fungi is a signature of selection for protection against the accumulation of toxic metabolic intermediates.gene cluster | gene orientation | inborn error of metabolism | secondary metabolism | specialized metabolism T here is a critical distinction between selection for a trait, which occurs at the phenotypic level, and selection of the underlying molecular genetic mechanisms that generate the trait (1). For example, some butterfly species avoid predation by mimicking the wing-pattern morphs of other butterflies that are toxic to birds (2, 3). In this case, predation avoidance selects for specific wing-pattern morphs, resulting in the selection of specific allelic combinations of genes in a supergene locus (4).The rise of molecular biology and subsequent abundance of genomic data have shifted the focus from phenotypes to genotypes, blurring the distinction between selection for and selection of. For example, many studies indicate that selection has sculpted the order and orientation of genes in eukaryotic genomes (5-13); although these analyses convincingly argue that specific genetic mechanisms are important in fine-tuning the structure of synteny on chromosomes, they implicitly assume that it is the genetic mechanisms themselves, rather than organismal phenotypes, that selection targets.One of the most conspicuous characteristics of fungal genomes is that the genes participating in a metabolic pathway are often physically linked, or clustered. Although both coordination of gene expression (5,6,(11)(12)(13)(14)(15)(16) and genetic linkage (7, 17) h...

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Section: Phytophthora Infestansmentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

McGary

Slot

Rokas

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The genetic and biochemical interest in this pathway comes from the fact that many severe human diseases (e.g., phenylketonuria, alcaptonuria, tyrosinemia, tyrosinosis, Richner-Hanhart syndrome, and hawkinsinuria) are associated with enzyme deficiencies in the catabolism of Phe and Tyr (16,19,24,32,52,73). First, Phe is transformed into Tyr by a pterin-dependent phenylalanine hydroxylase (PhhA), and later, a tyrosine aminotransferase (TyrB) catalyzes the conversion of Tyr into 4-hydroxyphenylpyruvate (4-OH-PhPyr), which is further transformed into 2,5-OH-PhAc by a 4-OH-PhPyr dioxygenase (Hpd) (Fig.…”

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confidence: 99%

The Homogentisate Pathway: a Central Catabolic Pathway Involved in the Degradation of l -Phenylalanine, l -Tyrosine, and 3-Hydroxyphenylacetate in Pseudomonas putida

et al. 2004

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Pseudomonas putida metabolizes Phe and Tyr through a peripheral pathway involving hydroxylation of Phe to Tyr (PhhAB), conversion of Tyr into 4-hydroxyphenylpyruvate (TyrB), and formation of homogentisate (Hpd) as the central intermediate. Homogentisate is then catabolized by a central catabolic pathway that involves three enzymes, homogentisate dioxygenase (HmgA), fumarylacetoacetate hydrolase (HmgB), and maleylacetoacetate isomerase (HmgC), finally yielding fumarate and acetoacetate. Whereas the phh, tyr, and hpd genes are not linked in the P. putida genome, the hmgABC genes appear to form a single transcriptional unit. Gel retardation assays and lacZ translational fusion experiments have shown that hmgR encodes a specific repressor that controls the inducible expression of the divergently transcribed hmgABC catabolic genes, and homogentisate is the inducer molecule. Footprinting analysis revealed that HmgR protects a region in the Phmg promoter that spans a 17-bp palindromic motif and an external direct repetition from position ؊16 to position 29 with respect to the transcription start site. The HmgR protein is thus the first IclR-type regulator that acts as a repressor of an aromatic catabolic pathway. We engineered a broad-host-range mobilizable catabolic cassette harboring the hmgABC, hpd, and tyrB genes that allows heterologous bacteria to use Tyr as a unique carbon and energy source. Remarkably, we show here that the catabolism of 3-hydroxyphenylacetate in P. putida U funnels also into the homogentisate central pathway, revealing that the hmg cluster is a key catabolic trait for biodegradation of a small number of aromatic compounds.

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“…Taking its considerable metabolic versatility into consideration, Peñalva previously proposed to use the filamentous fungus Aspergillus nidulans as an alternative to animal models for certain aspects of human metabolic diseases (12). Accordingly, other authors have provided a large amount of data about deficiencies not only in the phenylalanine/Tyr pathway but also in the branched-chain amino acid pathways (4,5,13,14).…”

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confidence: 99%

Fungal Metabolic Model for Tyrosinemia Type 3: Molecular Characterization of a Gene Encoding a 4-Hydroxy-Phenyl Pyruvate Dioxygenase from Aspergillus nidulans

et al. 2006

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A Fungal Perspective on Human Inborn Errors of Metabolism: Alkaptonuria and Beyond

Cited by 21 publications

References 26 publications

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

The Homogentisate Pathway: a Central Catabolic Pathway Involved in the Degradation of l -Phenylalanine, l -Tyrosine, and 3-Hydroxyphenylacetate in Pseudomonas putida

Fungal Metabolic Model for Tyrosinemia Type 3: Molecular Characterization of a Gene Encoding a 4-Hydroxy-Phenyl Pyruvate Dioxygenase from Aspergillus nidulans

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