Moonlighting proteins

Jeffery, Constance J.

doi:10.1016/s0968-0004(98)01335-8

Cited by 993 publications

(559 citation statements)

References 27 publications

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“…These proteins are thought to have evolved because they can provide cells with significant advantages, namely, the ability to increase the spectrum of metabolic activities without increasing the number of protein-coding genes, and the ability to coordinate different metabolic pathways (13). A previously unrecognized moonlighting mechanism emerges from our findings.…”

Section: Discussionmentioning

confidence: 73%

“…Moonlighting proteins represent a growing class of molecules that perform two or more different functions (13,45). These proteins are thought to have evolved because they can provide cells with significant advantages, namely, the ability to increase the spectrum of metabolic activities without increasing the number of protein-coding genes, and the ability to coordinate different metabolic pathways (13).…”

Section: Discussionmentioning

confidence: 99%

“…Moonlighting enzymes are a growing category of molecules that can accomplish multiple functions through a variety of mechanisms including, among others, localization to different cellular compartments, binding of different cofactors, and changes in oligomerization state (13). Mutations in moonlighting enzymes are predicted to contribute to the phenotypic variability of metabolic disorders (14).…”

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confidence: 99%

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Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Babady¹,

Pang

Elpeleg

et al. 2007

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

111

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The mitochondrial enzyme, dihydrolipoamide dehydrogenase (DLD), is essential for energy metabolism across eukaryotes. Here, conditions known to destabilize the DLD homodimer enabled the mouse, pig, or human enzyme to function as a protease. A catalytic dyad (S456 -E431) buried at the homodimer interface was identified. Serine protease inhibitors and an S456A or an E431A point mutation abolished the proteolytic activity, whereas other point mutations at the homodimer interface domain enhanced the proteolytic activity, causing partial or complete loss of DLD activity. In humans, mutations in the DLD homodimer interface have been linked to an atypical form of DLD deficiency. These findings reveal a previously unrecognized mechanism by which certain DLD mutations can simultaneously induce the loss of a primary metabolic activity and the gain of a moonlighting proteolytic activity. The latter could contribute to the metabolic derangement associated with DLD deficiency and represent a target for therapies of this condition.is a f lavindependent oxidoreductase required for the complete reaction of at least five different multienzyme complexes. In the mitochondrial matrix, the DLD homodimer functions as the E3 component of the pyruvate, ␣-ketoglutarate, and branchedchain amino acid-dehydrogenase complexes and the glycine cleavage system. In the context of these four multienzyme complexes, DLD utilizes dihydrolipoic acid and NAD ϩ to generate lipoic acid and NADH (1). The opposite reaction, from lipoic acid and NADH to dihydrolipoic acid and NAD ϩ , is catalyzed by the DLD homodimer in the context of the NAD ϩ -dependent peroxidase-peroxinitrate reductase of Mycobacterium tuberculosis (2). In addition, DLD has diaphorase activity, being able to catalyze the oxidation of NADH to NAD ϩ by using different electron acceptors such as O 2 , labile ferric iron (3), nitric oxide (4), and ubiquinone (5, 6). In this capacity, DLD is believed to primarily have a prooxidant role, achieved by reducing O 2 to a superoxide radical or ferric to ferrous iron, which in turn catalyzes production of hydroxyl radical through Fenton chemistry (3). However, the ability to scavenge nitric oxide and to reduce ubiquinone to ubiquinol suggests that the diaphorase activity of DLD may also have an antioxidant role (4-6). The oligomeric state of DLD can change from dimeric to monomeric or tetrameric depending on the pH in the mitochondrial matrix, and changes in the oligomeric state of the protein have been shown to correlate with a shift from DDL activity (only present in dimeric and tetrameric DLD) to diaphorase activity (present in both oligomeric and monomeric forms of the protein) (7,8). Thus, DLD represents a highly versatile oxidoreductase with multiple critical roles in energy metabolism and redox balance (2,7,(9)(10)(11)(12).Here, we found that DLD can also function as a moonlighting protease. Moonlighting enzymes are a growing category of molecules that can accomplish multiple functions through a variety of mechanisms including, among other...

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Babady¹,

Pang

Elpeleg

et al. 2007

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

111

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“…Enzymes such as aconitase, isocitrate dehydrogenase and Kgd2p (a subunit of KGDHC in yeast equivalent to E2k in mammal), are found to have two or more different functions (51)(52)(53)(54)(55)(56). For example, Kgd2p in yeast participates in both the tricarboxylic acid cycle and ϩ mtDNA maintenance (56).…”

Section: E2k Depletion and Cell Functionmentioning

confidence: 99%

Reduction in the E2k Subunit of the α-Ketoglutarate Dehydrogenase Complex Has Effects Independent of Complex Activity

Shi

Chen

et al. 2005

Journal of Biological Chemistry

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The activity of the ␣-ketoglutarate dehydrogenase complex (KGDHC) declines in brains of patients with several neurodegenerative diseases. KGDHC consists of multiple copies of E1k, E2k, and E3. E1k and E2k are unique to KGDHC and may have functions independent of the complex. The present study tested the consequences of different levels of diminished E2k mRNA on protein levels of the subunits, KGDHC activity, and physiological responses. Human embryonic kidney cells were stably transfected with an E2k sense or antisense expression vector. Sense control (E2k-mRNA-100) was compared with two clones in which the mRNA was reduced to 67% of control (E2k-mRNA-67) or to 30% of control (E2k-mRNA-30). The levels of the E2k protein in clones paralleled the reduction in mRNA, and E3 proteins were unaltered. Unexpectedly, the clone with the greatest reduction in E2k protein (E2k-mRNA-30) had a 40% increase in E1k protein. The activity of the complex was only 52% of normal in E2k-mRNA-67 clone, but was near normal (90%) in E2k-mRNA-30 clone. Subsequent experiments tested whether the physiological consequences of a reduction in E2k mRNA correlated more closely to E2k protein or to KGDHC activity. Growth rate, increased DCF-detectable reactive oxygen species, and cell death in response to added oxidant were proportional to E2k proteins, but not complex activity. These results were not predicted because subunits unique to KGDHC have never been manipulated in mammalian cells. These results suggest that in addition to its essential role in metabolism, the E2k component of KGDHC may have other novel roles.

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“…More recently, PGI has also been identified as the antigen involved in rheumatoid arthritis of a mouse line (13), as a specific inhibitor toward myofibril-bound serine proteinase (14), and as the surface antigen involved in sperm agglutination (15). Because very little is known about how PGI is precisely involved in these various biological processes, this moonlighting protein (16) has been the subject of intense investigations.…”

mentioning

confidence: 99%

The crystal structure of rabbit phosphoglucose isomerase complexed with 5-phospho- d -arabinonohydroxamic acid

Arsenieva

Hardré

Salmon

et al. 2002

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

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Phosphoglucose isomerase (EC 5.3.1.9) catalyzes the second step in glycolysis, the reversible isomerization of D-glucose 6-phosphate to D-fructose 6-phosphate. The reaction mechanism involves acid-base catalysis with proton transfer and proceeds through a cis-enediol(ate) intermediate. 5-Phospho-D-arabinonohydroxamic acid (5PAH) is a synthetic small molecule that resembles the reaction intermediate, differing only in that it has a nitrogen atom in place of C1. Hence, 5PAH is the best inhibitor of the isomerization reaction reported to date with a Ki of 2 ؋ 10 ؊7 M. Here we report the crystal structure of rabbit phosphoglucose isomerase complexed with 5PAH at 1.9 Å resolution. The interaction of 5PAH with amino acid residues in the enzyme active site supports a model of the catalytic mechanism in which Glu-357 transfers a proton between C1 and C2 and Arg-272 helps stabilize the intermediate. It also suggests a mechanism for proton transfer between O1 and O2. P hosphoglucose isomerase (PGI; EC 5.3.1.9) is a cytosolic glycolytic enzyme that catalyzes the reversible isomerization of D-glucose 6-phosphate (G6P) to D-fructose 6-phosphate (F6P). In addition to isomerase activity, PGI has been shown to display anomerase activity between pyranose anomers of G6P (1), between furanose anomers of F6P (2), and between those of D-mannose 6-phosphate (3), as well as C-2-epimerase activity on G6P (4). It also has roles in protein glycosylation, gluconeogenesis, and the pentose phosphate pathway (5). This central role in the metabolism of phosphorylated sugars explains the strong impact of PGI deficiency in humans (6, 7), as well as the interest as a therapeutic target in parasite metabolism (8). The PGI polypeptide chain, or perhaps a variation thereof, also has extracellular roles as neuroleukin, autocrine motility factor, and differentiation and maturation mediator (9-12). These proteins promote antibody secretion by mononuclear cells, tumor cell motility, and differentiation of leukemia cells and a promyelocytic cell line (HL-60 cells), respectively. More recently, PGI has also been identified as the antigen involved in rheumatoid arthritis of a mouse line (13), as a specific inhibitor toward myofibril-bound serine proteinase (14), and as the surface antigen involved in sperm agglutination (15). Because very little is known about how PGI is precisely involved in these various biological processes, this moonlighting protein (16) has been the subject of intense investigations.Biochemical characterization of PGI began over 50 years ago and includes inhibitor studies (1,(17)(18)(19)(20)(21)(22)(23)(24)(25), labeling studies (26-32), solvent exchange (33, 34), mutagenesis (35,36), and pH profile studies (20,37). A proposed multistep catalytic mechanism includes a ring-opening step followed by an isomerization step. The isomerization step proceeds via general acid-base catalysis with proton transfer. In the G6P to F6P direction, abstraction of the proton from C2 by an active site amino acid residue yields a 1,2-cis-enediol(ate) in...

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Moonlighting proteins

Cited by 993 publications

References 27 publications

Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Reduction in the E2k Subunit of the α-Ketoglutarate Dehydrogenase Complex Has Effects Independent of Complex Activity

The crystal structure of rabbit phosphoglucose isomerase complexed with 5-phospho- d -arabinonohydroxamic acid

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