====== Glycogen phosphorylase isoenzyme BB ======

===== Overview =====

Glycogen phosphorylase isoenzyme BB (GPBB) is an isoform of [[glycogen phosphorylase]] primarily expressed in the **brain** and **heart**. This enzyme plays a critical role in [[glycogen metabolism]] by catalyzing the phosphorolytic cleavage of glycogen to glucose-1-phosphate (G1P), which can be further metabolized to meet cellular energy demands.
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### **Key Characteristics**
- **Gene**: Encoded by the **PYGB** gene.
- **Tissue Distribution**:
  - High expression in the **brain** and **cardiac muscle**.
  - Functions to rapidly provide glucose-1-phosphate for energy, especially under conditions of stress or hypoxia.
- **Structure**:
  - Exists as a homodimer or homotetramer.
  - Includes regulatory sites for allosteric effectors and phosphorylation.

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### **Role in Metabolism**
1. **Energy Provision**:
   - Converts glycogen to glucose-1-phosphate, which enters glycolysis for ATP production.
   - Particularly important in the brain and heart, where constant energy supply is critical.

2. **Stress Response**:
   - GPBB is activated during hypoxia, ischemia, or other stress conditions, ensuring energy availability when glucose uptake is limited.

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### **Clinical Relevance**
1. **Ischemic Heart Disease**:
   - **GPBB as a Biomarker**:
     - During myocardial ischemia, GPBB is released into the bloodstream due to glycogen mobilization.
     - Elevated levels of GPBB in serum are used as a marker for **acute myocardial infarction (AMI)**.
   - **Diagnostic Value**:
     - GPBB is an early biomarker, detectable within 2-4 hours of the onset of ischemia, offering a diagnostic advantage over traditional markers like troponins or CK-MB.

2. **Neurological Disorders**:
   - Alterations in GPBB expression or function may impact brain energy metabolism, potentially playing a role in conditions like hypoxic-ischemic encephalopathy or neurodegenerative diseases.

3. **Glycogen Storage Diseases**:
   - Although rare, mutations in the PYGB gene could theoretically disrupt glycogen metabolism in tissues expressing GPBB, leading to energy deficits.

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### **Regulation**
- **Covalent Modification**:
  - Activated by phosphorylation via **phosphorylase kinase**.
  - Dephosphorylated by protein phosphatase-1, leading to inactivation.
- **Allosteric Regulation**:
  - **Activators**: AMP (signals low energy), calcium (via muscle contraction or neural activity).
  - **Inhibitors**: ATP, glucose-6-phosphate (indicators of energy sufficiency).

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### **Research and Therapeutic Potential**
1. **Cardiac Biomarker Development**:
   - GPBB inhibitors or modulators could have potential in managing ischemic heart disease by regulating glycogen mobilization.
2. **Neuroprotection**:
   - Targeting GPBB activity could mitigate energy deficits in ischemic or neurodegenerative conditions.
3. **Metabolic Engineering**:
   - Understanding GPBB’s role in energy metabolism could inspire novel therapeutic approaches for metabolic diseases.

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### **Diagnostic Use in Acute Myocardial Infarction**
- **Advantages**:
  - Early detection: Detectable soon after ischemia onset.
  - Complementary to troponins for more comprehensive diagnostic coverage.
- **Limitations**:
  - Lack of specificity to cardiac tissue (also expressed in the brain).
  - Requires correlation with other clinical findings for accurate diagnosis.


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Understanding the mechanistic basis for glioma [[temozolomide resistance]] is an important obstacle in developing an effective form of [[chemotherapy]].
[[Glycogenolysis]] is known to play an essential role in [[cell proliferation]] and potassium [[homeostasis]] and involves the glycogen phosphorylase isoenzyme BB ([[GPBB]]). 
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.))