Table 1 The non-canonical roles of metabolic enzymes

From: Non-canonical functions of enzymes facilitate cross-talk between cell metabolic and regulatory pathways

Enzyme

Pathway

Non-canonical role

Link

Ref

HK2

Glycolysis

Regulation of mTOR

Yes

74

  

Inhibitor of apoptosis

Yes

75

  

RNA regulation

Yes

112

PGI

Glycolysis

Extracellular cytokine

No

113

PFK-1

Glycolysis

Transcription

Yes

91

Aldolase

Glycolysis

AMPK regulation

Yes

65

  

F-actin binding

Yes

77

  

Endocytosis

Yes

114

  

Wnt signaling

n.d.

115

  

p53 regulation via DNA-PK

n.d.

116

  

RNA binding

n.d.

98

GAPDH

Glycolysis

Regulation of mTOR

Yes

72

  

RNA binding (T cells)

Yes

102

  

RNA binding

n.d./No

100

  

Transcription

Yes

117

  

Regulation of apoptosis

No

118

  

Cytoskeleton

No

118

  

Vesicular trafficking

No

118

  

DNA repair

n.d.

118

PGK

Glycolysis

Extracellular disulfide reductase

No

119

  

Protein kinase

No

4,5

  

RNA binding

n.d.

98

PGM

Glycolysis

Regulator of the cytoskeleton

No

39

ENO1

Glycolysis

Transcription (Myc)

n.d.

94

  

Transcription (Foxp3)

Yes

95

PKM2

Glycolysis

Protein kinase

n.d.

17

  

Transcription

n.d.

17

  

Extracellular (pro-angiogenesis)

No

120

LDH

Glycolysis

Transcription

Yes

121

  

RNA binding

n.d.

98

PDH

TCA cycle

Transcription (E2 subunit)

n.d.

122

ACO2

TCA cycle

RNA binding (Iron regulatory protein 1 (IRP1))

Yes

123

MDH1

TCA cycle

Transcription

No

61

FBP1

Gluconeogenesis

Transcription

No

47

  

MAPK signaling

No

48

TS

Thymidylate synthesis

RNA binding

Yes

103

DHFR

Thymidylate synthesis

RNA binding

Yes

103

MVK

Mevalonate pathway

RNA binding

Yes

108

GMPS

Purine synthesis

p53 stabilization

No

59

KHK

Fructose metabolism

Protein kinase

No

124

MTHFD2

Folate metabolism

Nuclear MTHFD2 promotes proliferation independent of enzymatic activity

No

125

HMGCS2

Ketone synthesis

Transcription (with PPARα)

No

35

EHHADH

Fatty acid degradation

Transcription (with PPARα)

No

38

  

RNA binding

n.d.

98

G6PD

Pentose phosphate pathway

RNA binding

n.d.

98

GDH

Glutamine metabolism

RNA binding

n.d.

98

SHMT

Serine synthesis

RNA binding

n.d.

98

  1. A list of the multifunctional enzymes identified to date in vertebrates, their non-canonical roles, the metabolic pathway they are associated with and whether their canonical and non-canonical functions are linked. In addition to these enzymes, numerous enzymes have been identified as RNA-binding proteins in RNA interactome screens but have yet to be validated. For a full list of these enzymes, please see ref.97
  2. HK2 hexokinase 2, PGI phosphoglucoisomerase, PFK-1 phosphofructokinase-1, GAPDH glyceraldehyde-3-phosphate dehydrogenase, PGK phosphoglycerate kinase, PGM phosphoglucomutase, ENO1 enolase 1, PKM2 pyruvate kinase muscle isoform 2, LDH lactate dehydrogenase, PDH pyruvate dehydrogenase, ACO2 aconitase 2, MDH1 malate dehydrogenase 1, FBP1 fructose-1,6-bisphospatase 1, TS thymidylate synthase, DHFR dihydrofolate reductase, MVK mevalonate kinase, GMPS Guanosine 5’-monophosphate synthase, KHK ketohexokinase, MTHFD2 methylenetetrahydrofolate dehydrogenase 2, HMGCS2 3-hydroxy-3-methylglutaryl-CoA synthase 2, EHHADH enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase, G6PD glucose-6-phosphate dehydrogenase, GDH glutamate dehydrogenase, SHMT serine hydroxymethyltransferase
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