From the Guidelines
When NADPH levels are low, cells meet their need for ribose 5-phosphate primarily by shifting the pentose phosphate pathway (PPP) toward the non-oxidative phase, as evidenced by the cellular metabolism of glucose and its derivatives 1. This shift allows cells to generate ribose 5-phosphate for nucleotide synthesis without producing NADPH. The pentose phosphate pathway is a mandatory pathway leading to NADPH synthesis, but it also plays a crucial role in providing ribose 5-phosphate for nucleic acid synthesis 1.
Key Points
- The pentose phosphate pathway has three main fates: glycolysis, glycogen synthesis, and the production of NADPH and ribose 5-phosphate 1.
- Cells can redirect glycolytic intermediates like fructose 6-phosphate and glyceraldehyde 3-phosphate through transketolase and transaldolase enzymes to produce ribose 5-phosphate without generating NADPH.
- The enzyme ribose-phosphate pyrophosphokinase can directly phosphorylate ribose to ribose 5-phosphate if ribose is available, providing an alternative pathway for ribose 5-phosphate production.
- The cell's ability to modulate these pathways is crucial because ribose 5-phosphate is essential for nucleotide synthesis and DNA/RNA production, while NADPH requirements fluctuate based on cellular redox status and biosynthetic demands 1.
Metabolic Adaptation
The metabolic adaptation of shifting the pentose phosphate pathway toward the non-oxidative phase ensures that nucleic acid synthesis can continue even when reducing power in the form of NADPH is not needed. This adaptation is critical for maintaining cellular homeostasis and supporting various cellular processes, including DNA and RNA synthesis.
Clinical Implications
Understanding the cellular metabolism of glucose and its derivatives is essential for appreciating the complex interactions between different metabolic pathways. The pentose phosphate pathway plays a critical role in maintaining cellular homeostasis, and its dysregulation can have significant implications for cellular function and overall health 1.
From the Research
Cellular Need for Ribose 5-Phosphate
When NADPH is low, cells can still meet their need for ribose 5-phosphate through the non-oxidative branch of the pentose phosphate pathway (PPP) 2. This branch is virtually ubiquitous and can metabolize glycolytic intermediates such as fructose 6-phosphate and glyceraldehyde 3-phosphate to yield ribose 5-phosphate for the synthesis of nucleic acids.
Alternative Pathways
In addition to the PPP, cells can also use other pathways to produce ribose 5-phosphate, such as:
- The Entner-Doudoroff pathway, which shares reactions with the PPP 2
- The Calvin cycle, which also shares reactions with the PPP 2
- The non-oxidative branch of the PPP can also supply glycolysis with intermediates derived from ribose 5-phosphate and vice versa, depending on the biochemical demand 2
Regulation of the Pentose Phosphate Pathway
The PPP is dynamically regulated through hierarchical interactions between transcriptome, proteome, and metabolome to meet the cellular demand for ribose 5-phosphate and NADPH 2, 3. The pathway is also regulated by various signals that affect transcription, post-translation, intracellular location, and interactions with other proteins 4.
Importance of the Pentose Phosphate Pathway
The PPP plays a critical role in maintaining cellular reduction-oxidation (redox) homeostasis and biosynthesis, and is involved in many human diseases, including cancer and diabetes 5, 3. The pathway is also essential for cell survival, as it provides NADPH required by many essential cellular systems, including antioxidant pathways and nitric oxide synthase 4.