Expression of the spermatogenic cell‐specific glyceraldehyde 3‐phosphate dehydrogenase (GAPDS) in rat testis

Welch, Janet L.; Barbee, Randy R.; Magyar, Patricia L.; Bunch, Donna O.; O’Brien, Deborah A.

doi:10.1002/mrd.20235

Cited by 43 publications

(47 citation statements)

References 44 publications

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“…This suggests that only the soluble sperm PK, which is not recognized by anti-PK-S, is present in the midpiece. Whether or not glycolysis is active in the midpiece of mature mammalian spermatozoa is still not clear because GAPDH has not yet been demonstrated in this part of sperm (Westhoff & Kamp 1997, Welch et al 2006. Interestingly, the head-midpiece junction showed PK-S staining (Fig.…”

Section: Localization Of Pk and Other Glycolytic Enzymes In Mammalianmentioning

confidence: 96%

“…Novel forms of glycolytic enzymes in sperm were identified from nucleotide sequences of GAPDH (GAPDH-S; Welch et al 1992Welch et al , 2000Welch et al , 2006 and HK (HK1-S; Mori et al 1993, Travis et al 1998. The corresponding amino acid sequences of both enzymes have unusual N-termini.…”

Section: Two Pks In Boar Spermatozoamentioning

confidence: 99%

“…Taken together these data would suggest glycolytic activity around the acrosome. On the other hand, GAPDH has not yet been found at the acrosome (Bunch et al 1998, Welch et al 2006, and there is no information as to whether the beforementioned enzymes are catalytically active or inactive remnants of protein synthesis during spermatogenesis (cf. Ramalho-Santos et al 2002, Kierszenbaum & Tres 2004 or have other than glycolytic functions as proposed for HK (Travis et al 1998).…”

Section: Localization Of Pk and Other Glycolytic Enzymes In Mammalianmentioning

confidence: 99%

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A novel pyruvate kinase (PK-S) from boar spermatozoa is localized at the fibrous sheath and the acrosome

Feiden

Stypa²,

Wolfrum³

et al. 2007

Reproduction

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Boar spermatozoa contain a novel pyruvate kinase (PK-S) that is tightly bound at the acrosome of the sperm head and at the fibrous sheath in the principal piece of the flagellum, while the midpiece contains a soluble pyruvate kinase (PK). PK-S could not be solubilized by detergents, but by trypsin with no loss of activity. Purified PK-S as well as PK-S still bound to cell structures and soluble sperm PK have all kinetics similar to those of rabbit muscle PK-M1. The PK-S subunit had a relative molecular mass of 64G 1!10 3 (nZ3), i.e. slightly higher than that of PK-M1, and carried an N-terminal extension (NH 2 -TSEAM-COOH) that is lacking in native PK-M1. Evidence is provided that PK-S is encoded by the PKM gene. Antibodies produced against the N-terminus of purified PK-S (NH 2 -TSEAMPKAHMDAG-COOH) were specific for PK-S as they did not react with somatic PKs or soluble sperm PK, while anti-PK-M1 recognized both sperm PKs. Immunofluorescence microscopy showed anti-PK-S to label the acrosome and the flagellar principal piece, whereas the midpiece containing the mitochondria was labelled only by anti-PK-M1. Immunogold labelling confirmed the localization of PK-S at the acrosome. In the principal piece, both polyclonal anti-PK-M1 and anti-PK-S were found at the fibrous sheath. Our results suggest that PK-S is a major component in the structural organization of glycolysis in boar spermatozoa.Reproduction (2007) 134 81-95

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Section: Localization Of Pk and Other Glycolytic Enzymes In Mammalianmentioning

confidence: 96%

Section: Two Pks In Boar Spermatozoamentioning

confidence: 99%

Section: Localization Of Pk and Other Glycolytic Enzymes In Mammalianmentioning

confidence: 99%

See 1 more Smart Citation

A novel pyruvate kinase (PK-S) from boar spermatozoa is localized at the fibrous sheath and the acrosome

Feiden

Stypa²,

Wolfrum³

et al. 2007

Reproduction

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show abstract

“…The most striking difference between GAPDS and GAPDH is the presence of an N-terminal polyproline region in GAPDS, which is 97 residues in rat (accession number AJ297631), 105 in mouse (3), and 72 in human (2). GAPDS is restricted to the principal piece of the sperm flagellum (1,2,4) where it is localized to the fibrous sheath (5), an association proposed to be mediated via the N-terminal polyproline extension.…”

mentioning

confidence: 99%

Structure of Insoluble Rat Sperm Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) via Heterotetramer Formation with Escherichia coli GAPDH Reveals Target for Contraceptive Design

Frayne

Taylor

Cameron

et al. 2009

Journal of Biological Chemistry

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Sperm glyceraldehyde-3-phosphate dehydrogenase has been shown to be a successful target for a non-hormonal contraceptive approach, but the agents tested to date have had unacceptable side effects. Obtaining the structure of the sperm-specific isoform to allow rational inhibitor design has therefore been a goal for a number of years but has proved intractable because of the insoluble nature of both native and recombinant protein. We have obtained soluble recombinant sperm glyceraldehyde-3-phosphate dehydrogenase as a heterotetramer with the Escherichia coli glyceraldehyde-3-phosphate dehydrogenase in a ratio of 1:3 and have solved the structure of the heterotetramer which we believe represents a novel strategy for structure determination of an insoluble protein.A structure was also obtained where glyceraldehyde 3-phosphate binds in the P s pocket in the active site of the sperm enzyme subunit in the presence of NAD. Modeling and comparison of the structures of human somatic and sperm-specific glyceraldehyde-3-phosphate dehydrogenase revealed few differences at the active site and hence rebut the long presumed structural specificity of 3-chlorolactaldehyde for the sperm isoform. The contraceptive activity of ␣-chlorohydrin and its apparent specificity for the sperm isoform in vivo are likely to be due to differences in metabolism to 3-chlorolactaldehyde in spermatozoa and somatic cells. However, further detailed analysis of the sperm glyceraldehyde-3-phosphate dehydrogenase structure revealed sites in the enzyme that do show significant difference compared with published somatic glyceraldehyde-3-phosphate dehydrogenase structures that could be exploited by structure-based drug design to identify leads for novel male contraceptives.Glyceraldehyde-3-phosphate dehydrogenase-S (GAPDS 3 in rat; GAPDH2 in human) is the sperm-specific isoform of GAPDH (1-3) and the sole GAPDH enzyme in sperm. GAPDS is highly conserved between species showing 94% identity between rat and mouse and 87% identity between rat and human. Within a particular species, GAPDS also shows significant sequence identity to its GAPDH paralogue, 70, 70, and 68% for rat, mouse, and human, respectively. The most striking difference between GAPDS and GAPDH is the presence of an N-terminal polyproline region in GAPDS, which is 97 residues in rat (accession number AJ297631), 105 in mouse (3), and 72 in human (2). GAPDS is restricted to the principal piece of the sperm flagellum (1, 2, 4) where it is localized to the fibrous sheath (5), an association proposed to be mediated via the N-terminal polyproline extension.GAPDS first came to prominence as a contraceptive target during the 1970s (6 -8). Investigations showed that treatment of sperm with ␣-chlorohydrin or a number of related compounds could inhibit GAPDS activity (9 -11), sperm motility (9 -13), and the fertilization of oocytes in vitro (14). The metabolite of these compounds, 3-chlorolactaldehyde (15-17), selectively inhibited GAPDS, having no effect on the activity of somatic cell GAPDH (18,19), pro...

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“…Since spermatogenesis relies on a strict metabolic cooperation between testicular cells, it is tempting to expect that targeting SC metabolism may be a good strategy to develop an effective and reversible male contraceptive. Particularly, enzymes responsible for cell's metabolism are highly conserved in all species and there are several glycolytic enzymes that present testis-specific isoforms [152].…”

Section: Metabolic Cooperation In Testis As a Concept For Male Contramentioning

confidence: 99%

Metabolic Cooperation in Testis as a Pharmacological Target: From Disease to Contraception

Alves¹,

Dias²,

Silva³

et al. 2015

CMP

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Abstract:The development of a "male pill" to control fertility is still a major challenge. Although women have several options to play an active role in the couple family planning, men are very limited in terms of contraceptive methods. Several approaches have been proposed to develop a male contraceptive and can be divided in two major groups: hormonal and non-hormonal methods. Within the testis, the somatic Sertoli cell (SC) is known as the "nurse cell" since it provides the physical and nutritional support for the developing germ cells. Moreover, adjacent SCs form the Sertoli/blood testis barrier (BTB), which divides the seminiferous epithelium into the basal and the apical compartments, controlling the passage of substances to the site where germ cells develop. Among the several functions of SC, its metabolism and the production of lactate, acetate and other metabolic factors are essential for the normal occurrence of spermatogenesis. In the last years, several works have highlighted that the metabolic cooperation established between SCs and developing germ cells is compromised in several diseases associated with male subfertility/infertility. Notably, several metabolismassociated proteins are specifically expressed in the testis. Thus, there are several evidences illustrating that the control of male fertility can be achieved by targeting testicular cells metabolism. Herein, we discuss the metabolic cooperation in testis as a potential pharmacological target to counteract subfertility/infertility promoted by several diseases, particularly metabolic diseases. We also discuss how it can contribute to the development of a male contraceptive.

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Expression of the spermatogenic cell‐specific glyceraldehyde 3‐phosphate dehydrogenase (GAPDS) in rat testis

Cited by 43 publications

References 44 publications

A novel pyruvate kinase (PK-S) from boar spermatozoa is localized at the fibrous sheath and the acrosome

A novel pyruvate kinase (PK-S) from boar spermatozoa is localized at the fibrous sheath and the acrosome

Structure of Insoluble Rat Sperm Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) via Heterotetramer Formation with Escherichia coli GAPDH Reveals Target for Contraceptive Design

Metabolic Cooperation in Testis as a Pharmacological Target: From Disease to Contraception

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