# NGLY1

## Overview
NGLY1 is a gene that encodes the enzyme N-glycanase 1, a cytosolic deglycosylation enzyme crucial for the endoplasmic reticulum-associated degradation (ERAD) pathway. This enzyme is responsible for removing N-linked glycans from misfolded glycoproteins, facilitating their degradation and maintaining protein quality control within cells (Miao2022Comprehensive; Pandey2022NGLY1). N-glycanase 1 is characterized by its three primary domains: the N-terminal PUB domain, the central transglutaminase-like core domain, and the C-terminal PAW domain, each contributing to its enzymatic function and protein interactions (Miao2022Comprehensive). The enzyme plays a significant role in cellular processes such as oxidative stress response and mitochondrial function, with its deficiency leading to mitochondrial abnormalities and increased oxidative stress (Kong2018Mitochondrial; Pandey2022NGLY1). Mutations in the NGLY1 gene result in NGLY1 deficiency, a rare autosomal recessive disorder with a wide range of clinical manifestations, underscoring the enzyme's importance in human health (Lipari2020NGLY1; Tong2023NGLY1).

## Structure
The NGLY1 protein is composed of 654 amino acids and features three primary domains: the N-terminal PUB domain, the central transglutaminase-like core domain, and the C-terminal PAW domain (Miao2022Comprehensive). The PUB domain, spanning amino acids 19-109, consists of a bundle of five α-helices and three-stranded parallel β-sheets, facilitating protein-protein interactions (Miao2022Comprehensive). The central transglutaminase-like domain contains a catalytic triad (Cys, His, Asp) essential for enzymatic activity, a zinc-binding motif, and a RAD23/HR23 binding motif, which are crucial for breaking the β-aspartyl-glycosyl-amine linkage in N-glycoproteins (Miao2022Comprehensive). The C-terminal PAW domain, characterized by a β-sandwich architecture, binds to high mannose moieties of N-linked oligosaccharide chains, enhancing the enzyme's affinity for N-glycans (Miao2022Comprehensive).

Post-translational modifications include phosphorylation, notably at Thr137, which is a hotspot for phosphorylation and has been implicated in cancer (Miao2022Comprehensive). Alternative splicing of NGLY1 results in different isoforms, some lacking parts of the functional domains, potentially affecting its role in ER-associated degradation (Miao2022Comprehensive).

## Function
NGLY1, or N-glycanase 1, is a cytosolic enzyme that plays a critical role in the deglycosylation process, which involves the removal of N-linked glycans from misfolded glycoproteins. This activity is essential for the endoplasmic reticulum-associated degradation (ERAD) pathway, a key mechanism for maintaining protein quality control by targeting misfolded proteins for proteasomal degradation (Miao2022Comprehensive; Pandey2022NGLY1). In healthy human cells, NGLY1 facilitates the degradation of misfolded glycoproteins, preventing their accumulation and potential toxicity, which is crucial for cellular homeostasis (Pandey2022NGLY1).

NGLY1 is involved in several cellular processes, including the regulation of oxidative stress response and mitochondrial function. It plays a role in the deglycosylation of NFE2L1, a transcription factor that regulates the expression of proteasome subunits, thereby alleviating cellular stress (Miao2022Comprehensive). NGLY1 is also implicated in mitochondrial homeostasis, as its deficiency leads to mitochondrial abnormalities and increased oxidative stress, highlighting its importance in maintaining mitochondrial integrity (Kong2018Mitochondrial; Pandey2022NGLY1). The enzyme's activity is vital for normal physiological processes and the proper functioning of multiple organ systems (Pandey2022NGLY1).

## Clinical Significance
Mutations in the NGLY1 gene lead to NGLY1 deficiency, a rare autosomal recessive disorder characterized by a range of multisystemic symptoms. These include severe global developmental delay, intellectual disability, hyperkinetic movement disorders, and peripheral neuropathy. Patients often experience alacrima or hypolacrima, transient elevation of liver transaminases, and progressive sensorimotor polyneuropathy. Additional symptoms can include seizures, reduced sweating, skeletal abnormalities, hearing loss, vision impairment, and adrenal insufficiency (Stanclift2022NGLY1; Lipari2020NGLY1; Tong2023NGLY1).

The disorder is caused by biallelic pathogenic variants in the NGLY1 gene, which result in the loss of function of the enzyme N-glycanase 1. This enzyme is crucial for the endoplasmic reticulum-associated degradation (ERAD) pathway, and its deficiency leads to the accumulation of misfolded glycoproteins, causing cellular damage, particularly in the brain, liver, and eyes (Enns2014Mutations; Pandey2022NGLY1).

NGLY1 deficiency is the first known congenital disorder of deglycosylation, and its clinical presentation can vary widely among patients. The estimated incidence in the U.S. is about 12 individuals born per year, though this may be underestimated due to diagnostic challenges (Stanclift2022NGLY1). There are currently no approved treatments, and management focuses on symptomatic relief (Tong2023NGLY1).

## Interactions
NGLY1, also known as N-glycanase 1, is involved in several critical protein interactions that facilitate its role in the endoplasmic reticulum-associated degradation (ERAD) pathway. One of the primary interactions is with the valosin-containing protein (VCP/p97), an ATPase that assists in the retrotranslocation of misfolded proteins from the ER to the cytosol. This interaction is mediated through the N-terminal PUB domain of NGLY1, which binds to VCP/p97, aiding in the deglycosylation process of misfolded glycoproteins (Miao2022Comprehensive; Pandey2022NGLY1).

NGLY1 also interacts with Rad23, a protein involved in nucleotide excision repair and proteasomal degradation. This interaction is conserved across species and is crucial for the function of NGLY1 in protein processing and degradation pathways (Suzuki2014The; Miao2022Comprehensive).

Additionally, NGLY1 is involved in the deglycosylation of NFE2L1 (NRF1), a transcription factor essential for the proteasome bounce-back response. The absence of NGLY1 leads to the accumulation of NFE2L1 at the ER, preventing its proper processing and activation, which underscores the importance of NGLY1-mediated deglycosylation for NFE2L1's release and function (Pandey2022NGLY1).


## References


[1. (Kong2018Mitochondrial) Jianping Kong, Min Peng, Julian Ostrovsky, Young Joon Kwon, Olga Oretsky, Elizabeth M. McCormick, Miao He, Yair Argon, and Marni J. Falk. Mitochondrial function requires ngly1. Mitochondrion, 38:6–16, January 2018. URL: http://dx.doi.org/10.1016/j.mito.2017.07.008, doi:10.1016/j.mito.2017.07.008. This article has 47 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.mito.2017.07.008)

[2. (Stanclift2022NGLY1) Caroline R. Stanclift, Selina S. Dwight, Kevin Lee, Quirine L. Eijkenboom, Matt Wilsey, Kristen Wilsey, Erica Sanford Kobayashi, Sandra Tong, and Matthew N. Bainbridge. Ngly1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the ngly1 registry. Orphanet Journal of Rare Diseases, December 2022. URL: http://dx.doi.org/10.1186/s13023-022-02592-3, doi:10.1186/s13023-022-02592-3. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s13023-022-02592-3)

[3. (Miao2022Comprehensive) Xiangguang Miao, Jin Wu, Hongping Chen, and Guanting Lu. Comprehensive analysis of the structure and function of peptide:n-glycanase 1 and relationship with congenital disorder of deglycosylation. Nutrients, 14(9):1690, April 2022. URL: http://dx.doi.org/10.3390/nu14091690, doi:10.3390/nu14091690. This article has 6 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/nu14091690)

[4. (Lipari2020NGLY1) Patrícia Lipari Pinto, Catarina Machado, Patrícia Janeiro, Juliette Dupont, Sofia Quintas, Ana Berta Sousa, and Ana Gaspar. Ngly1 deficiency—a rare congenital disorder of deglycosylation. JIMD Reports, 53(1):2–9, April 2020. URL: http://dx.doi.org/10.1002/jmd2.12108, doi:10.1002/jmd2.12108. This article has 24 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/jmd2.12108)

[5. (Tong2023NGLY1) Sandra Tong, Pamela Ventola, Christina H Frater, Jenna Klotz, Jennifer M Phillips, Srikanth Muppidi, Selina S Dwight, William F Mueller, Brendan J Beahm, Matt Wilsey, and Kevin J Lee. Ngly1 deficiency: a prospective natural history study. Human Molecular Genetics, 32(18):2787–2796, June 2023. URL: http://dx.doi.org/10.1093/hmg/ddad106, doi:10.1093/hmg/ddad106. This article has 1 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddad106)

[6. (Suzuki2014The) T. Suzuki. The cytoplasmic peptide:n-glycanase (ngly1)–basic science encounters a human genetic disorder. Journal of Biochemistry, 157(1):23–34, November 2014. URL: http://dx.doi.org/10.1093/jb/mvu068, doi:10.1093/jb/mvu068. This article has 58 citations and is from a peer-reviewed journal.](https://doi.org/10.1093/jb/mvu068)

[7. (Enns2014Mutations) Gregory M. Enns, Vandana Shashi, Matthew Bainbridge, Michael J. Gambello, Farah R. Zahir, Thomas Bast, Rebecca Crimian, Kelly Schoch, Julia Platt, Rachel Cox, Jonathan A. Bernstein, Mena Scavina, Rhonda S. Walter, Audrey Bibb, Melanie Jones, Madhuri Hegde, Brett H. Graham, Anna C. Need, Angelica Oviedo, Christian P. Schaaf, Sean Boyle, Atul J. Butte, Rong Chen, Michael J. Clark, Rajini Haraksingh, Tina M. Cowan, Ping He, Sylvie Langlois, Huda Y. Zoghbi, Michael Snyder, Richard A. Gibbs, Hudson H. Freeze, and David B. Goldstein. Mutations in ngly1 cause an inherited disorder of the endoplasmic reticulum–associated degradation pathway. Genetics in Medicine, 16(10):751–758, October 2014. URL: http://dx.doi.org/10.1038/gim.2014.22, doi:10.1038/gim.2014.22. This article has 185 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/gim.2014.22)

[8. (Pandey2022NGLY1) Ashutosh Pandey, Joshua M. Adams, Seung Yeop Han, and Hamed Jafar-Nejad. Ngly1 deficiency, a congenital disorder of deglycosylation: from disease gene function to pathophysiology. Cells, 11(7):1155, March 2022. URL: http://dx.doi.org/10.3390/cells11071155, doi:10.3390/cells11071155. This article has 20 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cells11071155)