Structural analyses to identify selective inhibitors of glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme

Danshina, Polina V.; Qu, Weidong; Temple, Brenda; Rojas, Rafael J.; Miley, Michael J.; Machius, Mischa; Betts, Laurie; O’Brien, Deborah A.

doi:10.1093/molehr/gaw016

Cited by 24 publications

(13 citation statements)

References 62 publications

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“…Recent studies further suggest that Galntl5 -deficient mice show male infertility owing to attenuated glycolytic enzymes (e.g., PGK2) required for motility and a patient diagnosed with asthenozoospermia had a mutation in the GALNTL5 gene. 157, 158, 159 …”

Section: Sperm-specific Glycolytic Enzyme In Adenosine Triphosphate (mentioning

confidence: 99%

The control of male fertility by spermatid-specific factors: searching for contraceptive targets from spermatozoon’s head to tail

et al. 2016

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Male infertility due to abnormal spermatozoa has been reported in both animals and humans, but its pathogenic causes, including genetic abnormalities, remain largely unknown. On the other hand, contraceptive options for men are limited, and a specific, reversible and safe method of male contraception has been a long-standing quest in medicine. Some progress has recently been made in exploring the effects of spermatid-specifical genetic factors in controlling male fertility. A comprehensive search of PubMed for articles and reviews published in English before July 2016 was carried out using the search terms ‘spermiogenesis failure', ‘globozoospermia', ‘spermatid-specific', ‘acrosome', ‘infertile', ‘manchette', ‘sperm connecting piece', ‘sperm annulus', ‘sperm ADAMs', ‘flagellar abnormalities', ‘sperm motility loss', ‘sperm ion exchanger' and ‘contraceptive targets'. Importantly, we have opted to focus on articles regarding spermatid-specific factors. Genetic studies to define the structure and physiology of sperm have shown that spermatozoa appear to be one of the most promising contraceptive targets. Here we summarize how these spermatid-specific factors regulate spermiogenesis and categorize them according to their localization and function from spermatid head to tail (e.g., acrosome, manchette, head-tail conjunction, annulus, principal piece of tail). In addition, we emphatically introduce small-molecule contraceptives, such as BRDT and PPP3CC/PPP3R2, which are currently being developed to target spermatogenic-specific proteins. We suggest that blocking the differentiation of haploid germ cells, which rarely affects early spermatogenic cell types and the testicular microenvironment, is a better choice than spermatogenic-specific proteins. The studies described here provide valuable information regarding the genetic and molecular defects causing male mouse infertility to improve our understanding of the importance of spermatid-specific factors in controlling fertility. Although a male contraceptive ‘pill' is still many years away, research into the production of new small-molecule contraceptives targeting spermatid-specific proteins is the right avenue.

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Section: Sperm-specific Glycolytic Enzyme In Adenosine Triphosphate (mentioning

confidence: 99%

The control of male fertility by spermatid-specific factors: searching for contraceptive targets from spermatozoon’s head to tail

et al. 2016

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“…Disruption of these enzymes leads to aberrant ATP production and sperm motility. However, their association with sperm quality requires investigation prior to their clinical application as promising diagnostic or contraceptive targets ( 21 , 22 ). In the present study, the key glycolytic enzymes GAPDHS, PGK2 and LDHC were comprehensively characterized in the human testis and spermatozoa, which provided novel information for understanding the regulation of sperm quality.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of sperm‑specific glycolytic enzymes are associated with poor sperm quality

Liu

Wang

et al. 2019

Mol Med Report

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The energy required for normal sperm function is mainly generated by glycolysis and oxidative phosphorylation. Testis-specific glycolytic enzymes are expressed in germ cells and present in mature spermatozoa. The objective of the present study was to investigate the association between aberrant expression of glycolytic enzymes and human sperm quality. In silico analysis of glyceraldehyde-3-phosphate dehydrogenase, testis-specific (GAPDHS), phosphoglycerate kinase 2 (PGK2) and lactate dehydrogenase (LDHC) identified that they were exclusively expressed in post-meiotic germ cells and this was validated in human testes using immunohistochemistry. Compared with the testes of young adults, markedly lower expression levels of these glycolytic enzymes were observed in the testes of elderly adults. Similarly, low levels were observed in immature and asthenozoospermic spermatozoa. The expression levels of GAPDHS, PGK2 and LDHC in the spermatozoa were closely correlated with progressive sperm motility. The results indicated that the expression of GAPDHS, PGK2 and LDHC in sperm may be associated with sperm quality, and there may be a similar molecular mechanism underlying sperm quality in immature and asthenozoospermic spermatozoa. This study reveals a close association of glycolytic enzymes with sperm quality. The data may greatly contribute to the molecular evaluation of sperm quality and the diagnosis and treatment of asthenozoospermia.

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“…Testis-specific glyceraldehyde-3-phosphate dehydrogenase glyceraldehyde-3-phoshoate (GAPDHS) was one of the key enzymes in the glycolysis pathway, and it mainly catalyzed the conversion of glyceraldehyde-3-phosphoric acid into glycerate-3-phosphate 18 . The GAPDHS knockout mice produced nonmotile sperm 19 , 20 . Fructose diphosphate aldolase A (ALDOA) catalyzed the conversion of fructose-1, 6-diphosphate into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate.…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteomics Reveal the Association between SPANX Proteins and Clinical Outcomes of Artificial Insemination with Donor Sperm

Wang

Xiang²,

et al. 2018

Sci Rep

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Semen analysis is used for diagnosing male infertility and evaluating male fertility for more than a century. However, the semen analysis simply represents the population characteristics of sperm. It is not a comprehensive assessment of the male reproductive potential. In this study, 20 semen samples from human sperm bank with distinctive artificial insemination with donor sperm (AID) clinical outcomes were collected and analyzed using a two-dimensional differential in-gel electrophoresis (2D-DIGE); 45 differentially expressed protein spots were obtained, and 26 proteins were identified. Most differentially expressed proteins were related to sperm motility, energy consumption, and structure. These identified proteins included several sperm proteins associated with the nucleus on the X chromosome (SPANX) proteins. This prospective study aimed to investigate the association between the expression levels of SPANX proteins and the AID clinical outcomes. The proteins identified in this study provided a reference for the molecular mechanism of sperm fertility and revealed a predictive value of the SPANX proteins.

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Structural analyses to identify selective inhibitors of glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme

Cited by 24 publications

References 62 publications

The control of male fertility by spermatid-specific factors: searching for contraceptive targets from spermatozoon’s head to tail

The control of male fertility by spermatid-specific factors: searching for contraceptive targets from spermatozoon’s head to tail

Aberrant expression of sperm‑specific glycolytic enzymes are associated with poor sperm quality

Comparative Proteomics Reveal the Association between SPANX Proteins and Clinical Outcomes of Artificial Insemination with Donor Sperm

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