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Seligman J, Newton GL, Fahey RC, Shalgi R, Kosower NS. Nonprotein thiols
and disulfides in rat epididymal spermatozoa and epididymal fluid: role of
-glutamyl-transpeptidase in sperm maturation. J Androl.
2005;26:629-637.
In their study, Seligman et al use the -glutamyl transpeptidase
(-GT) inhibitor acivicin to show that the enzyme -GT is actively
involved in catabolizing glutathione (GSH) to cysteine (CSH) in the caput
epididymidis. Furthermore, they propose that the oxidative potential generated
by this reaction facilitates oxidation of free thiols, thus forming GSSG,
GSSC, and CSSC moieties.
The Figure summarizes the
redox reactions that occur as a result of -GT activity in the
epididymal lumen (Drozdz et al,
1998; Paolicchi et al,
2002). These reactions, along with the activity of sperm NADPH
oxidase, generate a number of different reactive oxygen species (ROS).
Therefore, as is suggested in Seligman et al
(2005), there may be
sufficient ROS in the epididymal lumen to drive autoxiation of GSH and
CSH.
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However, apart from thiol auto-oxidation, GSSG might also be generated through GSH oxidation by the enzyme glutathione peroxidase. This enzyme is known to be secreted and active in the epididymis (Vernet et al, 2004), and it would be reasonable to assume that it is also involved with disulfide formation as spermatozoa traverse the caput epididymidis (Figure). There may be still other enzymes involved in free thiol oxidation in the epididymis. One such possibility mentioned in Seligman et al (2005) is sulfhydryl oxidase, which catalyzes the superoxide-dependent oxidation of GSH and CSH and has also been shown to have high activity in male reproductive tissues (Chang and Zirkin, 1978).
In recent years, -GT has emerged as an interesting enzyme to male
reproduction. Not only is it extremely abundant in epididymal tissues
(Agrawal and Vanha-Perttula,
1988), but also, the null mutation model has shown its presence to
be crucial for male fertility (Kumar et al,
2000). Reports have looked at -GT promotor regulation in
vivo (Kirby et al, 2004) with a
focus on epididymis-specific pathways for controlling enzyme expression.
However, despite the interest in -GT expression regulation, a key
question remained unanswered: what, in fact, is the enzyme's function in the
epididymis? Seligman et al
(2005) shed light on this
issue by demonstrating its active involvement in converting GSH to CSH,
particularly in the caput epididymidis. While this is a step toward
understanding the role of -GT in male reproductive tissues, the
findings presented in this article also open the door to further questions
about the enzyme's function.
It is known that several -GT isoforms exist in the epididymis
(Palladino and Hinton, 1994)
and that they are subject to segment-specific differential regulation by
testicular factors and testosterone
(Palladino and Hinton, 1994).
It would be of interest to identify which of these isoforms are involved with
the activities described by Seligman et al
(2005).
Another question that emerges from data presented in the article is the
exact location of -GT in the epididymis. While the authors state that
the enzyme is localized in the epididymal epithelium, the continued conversion
of free thiols to disulfides in the presence of epididymal fluid alone
suggests that a secreted form of -GT also exists. Immunohistologic
analysis of this enzyme would be a useful follow-up to what we now know about
its role in the epididymis.
One of the particularly novel findings by Seligman et al
(2005) is that the presence of
oxidized thiols is essential and, perhaps, sufficient for disulfide bond
formation in sperm. This poses a question regarding the role of the enzyme
hydroperoxide glutathione peroxidase (PHGPx, also known as glutathione
peroxidase 4) in sperm maturation. Numerous publications pertaining to the
role of PHGPx in sperm nuclear disulfide formation have established the
apparent importance of this enzyme to the process
(Tramer et al, 2002; Vernet et al, 2004). The study
by Seligman et al (2005) opens
the possibility of the existence of an alternate pathway to thiol oxidation in
sperm. Immunohistologic examination would once again be an interesting
approach to help resolve this issue, as staining for both PHGPx and -GT
could help dissociate the involvement of each enzyme in sperm maturation.
Apart from understanding the function of -GT in the epididymis, the
study also touches on the question of protein and nonprotein thiols in the
sperm nucleus. As illustrated in the
Figure, mature sperm have a
mixed disulfide population, where protamines can form disulfide bonds either
with other protamines or with nonprotein thiols such as GSH and CSH. However,
we currently have little knowledge regarding what types of disulfides are
present, the reactions by which they are formed, and the relative
contributions of each. Future studies on this topic could provide valuable
information for building an accurate model of sperm chromatin packaging.
Overall, the findings presented by Seligman et al
(2005) are an important step
toward understanding sperm nuclear stabilization. They offer a new
interpretation of clinical data that correlate infertility and abnormal sperm
with both under- or overoxidation of nuclear thiols
(Rufas et al, 1991;
Evenson et al, 2000;
Zini et al, 2001) and suggest
the involvement of -GT in these pathologies. Furthermore, the study
once again reminds us of the duality of oxidative processes; antioxidants can
turn into oxidants, which drive sperm thiols to form stable relationships.
 |
References |
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 Top References |
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Chang TSK, Zirkin BR. Distribution of sulfhydryl oxidase activity in the rat and hamster male reproductive tract. Biol Reprod. 1978;17: 745 -748.
Drozdz R, Parmentier C, Hachad H, Leroy P, Siest G, Wellman M. Gamma-glutamyltransferase dependent generation of reactive oxygen species from a glutathione/transferrin system. Free Radic Biol Med. 1998; 25: 786 -792.[CrossRef][Medline]
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Seligman J, Newton GL, Fahey RC, Shalgi R, Kosower NS. Nonprotein
thiols and disulfides in rat epididymal spermatozoa and epididymal fluid: role
of -glutamyl-transpeptidase in sperm maturation. J
Androl. 2005;26: 629
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Tramer F, Micali F, Sandri G, Bertoni A, Lenzi A, Gandini L, Panfili E. Enzymatic and immunochemical evaluation of phospholipid hydroperoxide glutathione peroxidase (PHGPx) in testes and epididymal spermatozoa of rats of different ages. Int J Androl. 2002; 25: 72 -83.[CrossRef][Medline]
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