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Benzylisoquinoline Alkaloids Biosynthesis of BERBERINE (Berberine bridge enzyme)

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It is known that the immediate precursor of protoberberine alkaloids in plants is . Berberine is an alkaloid derived from . and 4-hydroxypyruvic acid both come from L-Tyr. Although two molecules are used in the biosynthetic pathway, only the fragment of the ring system is formed via DOPA, the remaining carbon atoms come from via 4-hydroxyphenylacetaldehyde. loses carbon dioxide to form 1. Likewise, 4-hydroxypyruvic acid also loses carbon dioxide to form 4-hydroxyphenyl-acetaldehyde 2. 1 then reacts with 4-hydroxy-phenylacetaldehyde 2 to form (S)-norcolaurine 3 in a reaction similar to the . After oxidation and methylation by , 4 is formed. serves as a pivotal intermediate to other alkaloids. Oxidation of the then occurs and an is formed 5. In a Mannich-like reaction the ortho position to the phenol is nucleophilic, and electrons are pushed to form 6. Product 6 then undergoes to form (S)-scoulerine which is then methylated by SAM to form (S)-tetrahydrocolumbamine 7. Product 7 is then oxidized to form the ring from the ortho-methoxyphenol, via an O2-, NADPH- and cytochrome P-450-dependent enzyme. giving (S)-canadine 8. (S)-canadine is then oxidized to give the quaternary isoquinolinium system of berberine. This happens in two separate oxidation steps, both requiring molecular oxygen, with H2O2 and H2O produced in the successive processes.

Berberine Biosynthesis.

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Berberine seems to act as an herbal antidepressant and a neuroprotector against neurodegenerative disorders. Berberine inhibits (POP) in a dose-dependent manner. Berberine is also known to bind like many synthetic antidepressant drugs. As berberine is a natural compound that has been safely administered to humans, preliminary results suggest the initiation of clinical trials in patients with depression, bipolar affective disorder, schizophrenia, or related diseases in which cognitive capabilities are affected, with either the extract or pure berberine. New experimental results suggest that berberine may have a potential of inhibition and prevention of (AD) mainly through both cholinesterase (ChEs)inhibitory and beta-amyloids pathways, and additionally through antioxidant capacities.

Berberine lowers elevated blood total , LDL cholesterol, and aterogenic (apo B) (Apo B), but the mechanism of action is distinct from . Berberine reduces LDL cholesterol by upregulating LDLR mRNA expression posttranscriptionally while downregulating the transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9), a natural inhibitor of (LDLR), and increasing in the liver the expression of LDL receptors through extracellular signal-regulated kinase (ERK) signaling pathway, while statins inhibit cholesterol synthesis in the liver by blocking HMG-CoA-reduktase. This explains why berberine does not cause side effects typical to statins. Berberine and synergistically inhibit cholesterol absorption in hamsters. Berberin seems to improve the arterial endothelial function in humans. Berberine activates (AMPK), specifically (ERK), which plays a central role in glucose and lipid metabolism, suppresses proinflammatory cystokines, and reduces MMP-9 and EMMPRIN expression, which are all beneficial changes for heart health. Morevover, berberine reduces hepatic fat content in the rats of non-alcoholic fatty liver disease (NAFLD). Berberine also prevents proliferation of hepatic stellate cells (HSCs), which are central for the development of fibrosis during liver injury.