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Page 2 of 16 Thirugnanam et al. Vessel Plus 2020;4:26 I http://dx.doi.org/10.20517/2574-1209.2020.18

include more than 1000 mammalian proteins. The sequence similarity of protein kinases in their catalytic
[1]
domains indicates that they have evolved from a common precursor protein . Protein kinases play an
important role in signal transduction by phosphorylating specific amino acids of downstream substrates
and catalyzing the conversion of substrate proteins into phosphoproteins. The phosphorylation can
be reversed by protein phosphatases. Protein phosphorylation is one of the common forms of cellular
regulation during various cellular processes including metabolism, proliferation, differentiation, motility,
survival, and death. Protein phosphorylation, first described in eukaryotes, is a post-translational
modification of proteins whereby a phosphate group is covalently attached to a serine, threonine, or
[2,3]
tyrosine residue . Eukaryotic serine (S), threonine (T), and tyrosine (Y) kinases are grouped together in
the eukaryotic protein kinase superfamily based on sequence homology in their kinase domains.

The two main groups of the superfamily, the serine/threonine kinases and the tyrosine kinases can be
subdivided further into smaller families which are composed of enzymes that show similar substrate
[4]
specificities and mode of regulation . Serine/threonine kinases (STKs) transfer phosphate group from
Adenosine triphosphate (ATP) to the OH (hydroxyl) group on the side chain of a serine or threonine
amino acid residue in a protein, producing ADP and a phosphoprotein. STKs are involved in the
regulation of cellular proliferation, programmed cell death (apoptosis), cell differentiation, and embryonic
development . Similar to STKs, tyrosine-kinase enzymes transfer a phosphate group from ATP to a
[5]
tyrosine residue in a protein. Tyrosine-protein kinases are classified into two main groups: (1) receptor
tyrosine kinases, which are attributed to transmembrane proteins involved in signal transduction and
[6]
play key roles in growth, differentiation, metabolism, adhesion, motility, death, and oncogenesis ; and
(2) cytoplasmic/non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in
[7]
cell differentiation, motility, proliferation, and survival . Several kinases are activated by auto- or trans-
[8]
phosphorylation on at least one S/T/Y residue in the activation loop by a second kinase .
Sucrose nonfermenting 1-related kinase (SNRK) is a novel member of AMP-activated protein kinase
(AMPK) subfamily of STKs. The AMPK family members share sequence homology with other members
of the family in their catalytic domain . SNRK was first identified in 1996 in 3T3-L1 adipocytes where its
[4]
[9]
expression was observed during differentiation into an adipocyte-like cell . SNRK is a monomeric enzyme
containing a nuclear localization signal (NLS) domain, an ATP-binding domain, and an active S/T kinase
[10]
domain with a conserved T-loop threonine residue (T173) [Figure 1]. Kinases that regulate SNRK activity
have been identified. For example, liver kinase B1 (LKB1) phosphorylates multiple kinases especially the
AMPK family, including SNRK. LKB1 phosphorylates substrates (AMPK and AMPK-related kinases) at
[11]
the T-loop threonine residue . Unlike many AMPKs, SNRK does not require an additional stimulus for
[12]
activation such as increased AMP:ATP ratio within a cell. SNRK also phosphorylates several proteins
including Rho-associated kinase (ROCK) [12-19] . Thus, SNRK regulation and its associated signaling partners
and pathways are emerging areas of research. Further, SNRK’s role in various cell types in metabolic tissues
such as cardiac and adipose is also emerging. We have compiled a list of publications that suggests SNRK’s
role in numerous cell types, and its influence on the underlying cellular processes [Table 1]. In this review,
we focus on SNRK’s role in the regulation of metabolism and inflammation in heart and adipose tissue, and
the impact of SNRK’s dysregulation on metabolic and inflammatory-associated disease conditions.

SNRK: STRUCTURE, EXPRESSION, AMPK FAMILY ASSOCIATION AND ACTIVATORS
SNRK structure
The AMPK family members have been extensively characterized. These kinase enzymes include AMPKα1,
[25]
AMPKα2, MARK1/2/3/4, SIK1/2/3, NUAK1/2, BRSK1/2, and MELK . The AMPK protein family
contains similar domain organization, namely, an N-terminal kinase domain and an adjacent ubiquitin-
associated (UBA) domain. SNRK is a novel member of the AMPK family, and a 2.9Å resolution crystal
[10]
structure of its N-terminal fragment containing the kinase and adjacent UBA domain is now available .