The evolving world of pseudoenzymes: proteins, prejudice and zombies

Eyers, Patrick A.; Murphy, James M.

doi:10.1186/s12915-016-0322-x

Cited by 77 publications

(62 citation statements)

References 31 publications

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“…The appearance and retention of pseudoenzymes during evolution in essentially all enzyme families suggests that these domains are malleable templates that can be coopted for new biological functions when required 88, 89, 90. This is clearly demonstrated within the human protein kinase superfamily by the three TRIB pseudokinases, which together control large networks of cellular signaling pathways, many of which are known to be dysregulated in disease.…”

Section: Discussionmentioning

confidence: 99%

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

Eyers

Keeshan

Kannan

2017

Trends in Cell Biology

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The Tribbles (TRIB) pseudokinases control multiple aspects of eukaryotic cell biology and evolved unique features distinguishing them from all other protein kinases. The atypical pseudokinase domain retains a regulated binding platform for substrates, which are ubiquitinated by context-specific E3 ligases. This plastic configuration has also been exploited as a scaffold to support the modulation of canonical MAPK and AKT modules. In this review, we discuss the evolution of TRIBs and their roles in vertebrate cell biology. TRIB2 is the most ancestral member of the family, whereas the emergence of TRIB3 homologs in mammals supports additional biological roles, many of which are currently being dissected. Given their pleiotropic role in diseases, the unusual TRIB pseudokinase conformation provides a highly attractive opportunity for drug design.

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Section: Discussionmentioning

confidence: 99%

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

Eyers

Keeshan

Kannan

2017

Trends in Cell Biology

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190

207

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“…Pseudoenzymes often function as regulators in biological systems. 35,36,[39][40][41] Pseudoenzymes contain a protein domain that resembles a catalytically active counterpart, but lacks the predicted enzymatic activity. 39,40 At least 10% of mammalian enzyme domains are predicted to be catalytically inactive.…”

Section: Discussionmentioning

confidence: 99%

“…35,36,[39][40][41] Pseudoenzymes contain a protein domain that resembles a catalytically active counterpart, but lacks the predicted enzymatic activity. 39,40 At least 10% of mammalian enzyme domains are predicted to be catalytically inactive. 35,41 Well-described classes of pseudoenzymes include pseudokinases and pseudophosphatases, which affect biology through their often poorly understood regulatory activities.…”

Section: Discussionmentioning

confidence: 99%

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

et al. 2019

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Pantothenate kinase generates 4′‐phosphopantothenate in the first and rate‐determining step of coenzyme A (CoA) biosynthesis. The human genome encodes three well‐characterized and nearly identical pantothenate kinases (PANK1‐3) plus a putative bifunctional protein (PANK4) with a predicted amino‐terminal pantothenate kinase domain fused to a carboxy‐terminal phosphatase domain. Structural and phylogenetic analyses show that all active, characterized PANKs contain the key catalytic residues Glu138 and Arg207 (HsPANK3 numbering). However, all amniote PANK4s, including human PANK4, encode Glu138Val and Arg207Trp substitutions which are predicted to inactivate kinase activity. Biochemical analysis corroborates bioinformatic predictions—human PANK4 lacks pantothenate kinase activity. Introducing Glu138Val and Arg207Trp substitutions to the human PANK3 and plant PANK4 abolished their robust pantothenate kinase activity. Introducing both catalytic residues back into human PANK4 restored kinase activity, but only to a low level. This result suggests that epistatic changes to the rest of the protein already reduced the kinase activity prior to mutation of the catalytic residues in the course of evolution. The PANK4 from frog, an anamniote living relative encoding the catalytically active residues, had only a low level of kinase activity, supporting the view that HsPANK4 had reduced kinase activity prior to the catalytic residue substitutions in amniotes. Together, our data show that human PANK4 is a pseudo‐pantothenate kinase—a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi. The Glu138Val and Arg207Trp substitutions in amniotes (HsPANK3 numbering) completely deactivated the pantothenate kinase activity that had already been reduced by prior epistatic mutations.

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“…85 Thus, AtPDX1.2 can be classified as a pseudoenzyme, i.e. looks like an enzyme but is not 86 (sometimes also referred to as Zombie enzymes (Eyers & Murphy, 2016), based on analogy to a 87 reanimated corpse). Recently, the recognition of pseudoenzymes as substantial cellular regulators 88 has been highlighted as an important emerging area of molecular biology .…”

Section: Introduction 47mentioning

confidence: 99%

The Pseudoenzyme PDX1.2 Sustains Vitamin B₆ Biosynthesis as a Function of Heat Stress

2017

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One sentence summary: Expression of PDX1.2 is regulated by the HSFA1 transcription factor 15family and is an important abiotic stress tolerance strategy in most eudicots that is not utilized by 16 monocots such as grasses. ABSTRACT 28Plants sense temperature changes and respond by altering growth and metabolic activity to 29 acclimate to the altered environmental conditions. The B vitamins give rise to vital coenzymes that 30 are indispensable for growth and development but their inherent reactive nature renders them prone 31 to destruction especially under stress conditions. Therefore, plant survival strategies would be 32 expected to include mechanisms to sustain B vitamin supply under demanding circumstances. Here, 33 using the example of vitamin B 6 , we investigate the regulation of biosynthesis across eudicot and 34 monocot species under heat stress. Most eudicots carry a pseudoenzyme PDX1.2 that is a non-35 catalytic homolog of the PDX1 subunit of the vitamin B 6 biosynthesis protein machinery, 36 PYRIDOXINE SYNTHASE. Using Arabidopsis and tomato as models, we show that PDX1.2 is 37 transcriptionally regulated by the HSFA1 transcription factor family. Monocots only carry catalytic 38 PDX1 homologs but do not respond to heat stress as demonstrated for rice and maize, suggesting 39 fundamental differences in the regulation of vitamin B 6 biosynthesis across the two lineages. 40Investigation of the molecular mechanism of PDX1.2 transcription reveals two alternative 41 transcriptional start sites one of which is exclusive to heat stress. Further data suggest that PDX1.2 42 leads to stabilization of the catalytic PDX1s under heat stress conditions, which would serve to 43 maintain vitamin B 6 homeostasis in times of need in eudicots that carry this gene. Our analyses 44indicate an important abiotic stress tolerance strategy in several eudicots, which has not been 45 evolutionarily adapted (or is not required) by monocots such as grasses. INTRODUCTION 47The B vitamins are essential for survival of all organisms, as they provide important coenzymes for 48 numerous cellular proteins and have more recently been implicated in non-coenzyme related 49 activities (Colinas & Fitzpatrick, 2015). Plants are autonomous for these compounds 50 biosynthesizing them de novo from relatively simple precursors and are a major source of 51 micronutrients required by animals, including humans (Fitzpatrick et al., 2012). Being chemically 52 reactive by nature as coenzymes and vital for cellular function, it is important that homeostasis of B 53 vitamins is maintained with supply and demand of these compounds needing to be strictly 54 coordinated. In this context, the devastating developmental and physiological effects that 55 deficiencies in the B vitamin compounds can have on an organism, in particular humans, is 56 thoroughly documented, as well as consequences of oversupply (Kennedy, 2016, Spector & 57 Johanson, 2007. In plants, while there are numerous reports on B vitamin metabolism per se 58 (biosynthesis, transport), th...

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The evolving world of pseudoenzymes: proteins, prejudice and zombies

Cited by 77 publications

References 31 publications

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

The Pseudoenzyme PDX1.2 Sustains Vitamin B₆ Biosynthesis as a Function of Heat Stress

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The evolving world of pseudoenzymes: proteins, prejudice and zombies

Cited by 77 publications

References 31 publications

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

The Pseudoenzyme PDX1.2 Sustains Vitamin B6 Biosynthesis as a Function of Heat Stress

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The Pseudoenzyme PDX1.2 Sustains Vitamin B₆ Biosynthesis as a Function of Heat Stress