Table 1.

The non-canonical roles of metabolic enzymes

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

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

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