ABSTRACT

A dozen of selenium (Se)-dependent proteins identified in mammals (Table 17.1) share at least two distinct features. First, Se in the polypeptide is covalently bound in a moiety of selenocysteine encoded by thymine-guanine-adenine (TGA), normally a stop codon. Second, Se availability regulates expression of not only their protein and activity, but also their mRNA levels in cells or tissues. In prokaryotes, Se is incorporated into selenocysteine co-translationally. The process is directed by a special stem-loop structure of mRNA, requiring four unique gene products. Much less is certain about the eukaryotic Se-incorporation. The dramatic impact of Se status on selenoprotein gene expression and the differential responses of various selenoproteins to Se depletion or repletion are fascinating, although the mechanism of Se regulation and the physiological implication remain largely unclear. A comprehensive understanding of selenoprotein biosynthesis in eukaryotes would help us in tackling these problems, and gene-knockout mouse models provide us with unprecedented tools. Because cellular glutathione peroxidase (EC 1.11.1.9; GPX1) is the first identified, 1,2 the most abundant, 3 and the best-studied biochemical functional form of body Se, this chapter focuses on the expression and Se regulation of GPX1 and its three family members in comparison with those of other selenoproteins. Characterized Mammalian Selenoproteins

Name

Size (kDa)

Role

Distribution

1. Glutathione peroxidase (GPX) family

GPX1 or cGPX (cyotosolic, cellular, or classical GPX)

88

Antioxidative, GSH-dependent reduction of hydroperoxides

Ubiquitous

GPX2 or GPX-GI (gastrointestinal GPX)

88

GSH-dependent reduction of hydroperoxides

Mainly gastrointestinal tract

GPX3 or plasma GPX (extracellular GPX)

92

GSH-dependent reduction of hydroperoxides

Plasma and interstitial and extracellular space in lung, intestine, and kidney

GPX4 or PHGPX (phospholipid hydroperoxide GPX)

19

Reduction of phospholipid hydroperoxides

Ubiquitous, abundant in testis

2. Iodothyronine 5′-deiodinases (ID)

ID1 (type 1)

28

Conversion of T4 to T3, inactivation of T4 and T3

Brain, kidney, liver, and thyroid

ID2 (type 2)

30

Conversion of T4 to T3

Adipose tissue heart, muscle, pituitary, and thyroid

ID3 (type 3)

32

Inactivation of T4 and T3

Brain, placenta, and skin

3. Thioredoxin reductases (TR)

TR1

110

NADPH-dependent reduction of thioredoxin

Ubiquitous

TR2

130

NADPH-dependent reduction of thioredoxin

Adrenal, heart, kidney, testis

TR3

114

NADPH-dependent reduction of thioredoxin

Ubiquitous

4. Selenophosphate synthetase

48

ATP-dependent activation of selenium for biosynthesis of selenocysteine

Ubiquitous

5. Selenoproteins (Sel)

Sel-P

57

Unknown

Plasma

Sel-W

10

Unknown

Ubiquitous

15-kD Sel

15

Unknown

Ubiquitous