Glycogen Phosphorylase L [Neurosurgery Wiki]

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====== Glycogen Phosphorylase L ======

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**Glycogen Phosphorylase L (PYGL): Overview**

[[Glycogen]] phosphorylase L ([[PYGL]]) is an isoform of [[glycogen phosphorylase]] predominantly expressed in the liver. This enzyme plays a crucial role in [[glycogen metabolism]], catalyzing the breakdown of glycogen into glucose-1-phosphate (G1P). This process is vital for maintaining [[blood glucose]] levels, particularly during fasting or periods of increased energy demand.

### **Structure and Function**
- **Gene**: The PYGL gene encodes the liver isoform of glycogen phosphorylase.
- **Function**: The enzyme facilitates the phosphorolysis of glycogen, cleaving α-1,4 glycosidic bonds. It is regulated by hormonal signals and allosteric interactions.
- **Activity Regulation**:
  - **Hormonal**: Activated by glucagon and epinephrine via cAMP-dependent phosphorylation, promoting glycogen breakdown in response to low blood glucose levels.
  - **Allosteric**: Inhibited by glucose and ATP, indicating sufficient energy supply. Activated by AMP during low energy states.

### **Clinical Relevance**
- **Glycogen Storage Disease Type VI (Hers Disease)**:
  - **Cause**: Mutations in the PYGL gene lead to reduced or absent glycogen phosphorylase activity in the liver.
  - **Symptoms**: Hepatomegaly, mild fasting hypoglycemia, growth retardation, and ketosis.
  - **Diagnosis**: Based on genetic testing and liver biopsy showing abnormal glycogen storage.
  - **Management**: Dietary interventions to prevent hypoglycemia, including frequent meals and cornstarch supplementation.

### **Biological Significance**
- PYGL is crucial for glucose homeostasis. The liver's ability to mobilize glycogen stores depends on this enzyme, especially during fasting or stress.
- Dysfunction in PYGL has downstream effects on metabolism, highlighting its significance in energy regulation and potential therapeutic targeting for metabolic disorders.

### **Research and Therapeutic Insights**
- **Potential Target in Metabolic Disorders**: Modulating PYGL activity could be explored in diseases like diabetes, where glycogen breakdown plays a role in hyperglycemia.
- **Drug Development**: Inhibitors or activators of PYGL could provide therapeutic strategies for conditions involving glycogen storage and glucose metabolism. 


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[[Glycogenolysis]] is known to play an essential role in [[cell proliferation]] and potassium homeostasis and involves the glycogen phosphorylase isoenzyme BB ([[GPBB]]). In this investigation, plasma GPBB was correlated with TMZ-resistance. Elevated plasma GPBB concentrations were found to be more frequent in a TMZ-resistant cohort of patients with poor survival rates. TMZ inhibits cell proliferation and induces TMZ resistance by upregulating the expression of O(6)-methylguanine-DNA methyltransferase (MGMT). This process requires glycogenolysis, which was confirmed herein by treatment with 1,4-dideoxy-1,4-imino-D-arabinitol hydrochloride, a glycogenolysis inhibitor and a special GPBB inhibitor. Acute TMZ treatment leads to upregulation of [Ca2+]i, extracellular-regulated kinase (ERK)1/2 phosphorylation, and chronic TMZ treatment leads to upregulation of the expression of Na,K-ATPase, ERK1/2, and MGMT protein. Upregulation was abolished for each of these by inhibitors of transient receptor potential channel 1 and the inositol trisphosphate receptor. L-channel [Ca2+]i inhibitors and RyR antagonists had no such effect. These results demonstrate that [Ca2+]i-dependent glycogenolysis participates in acquired glioma TMZ-resistance by upregulating MGMT via a Na,K-ATPase/ERK1/2 signaling pathway. GPBB and glycogenolysis may therefore represent novel therapeutic targets for overcoming TMZ-resistant gliomas
((Xu J, Zhang Y, Guo X, Sun T. Glycogenolysis in Acquired Glioma Resistance to Temozolomide: A Role for the [Ca2+]i-dependent Activation of Na,K-ATPase/ERK1/2 Signaling. Front Pharmacol. 2018 Aug 7;9:873. doi: 10.3389/fphar.2018.00873. PMID: 30131700; PMCID: PMC6090282.)).