The Phorbol-Proof Kinase

The one member of its family that irritant plant compounds physically cannot switch on.

Sphingosine-1-phosphate increases it.

A second key that fits the same lock — and a lock the dangerous key cannot turn. 'S1P induced Thr410 phosphorylation of PKC zeta in 3T3-L1 adipocytes and activated recombinant PKC zeta in kinase assays. S1P-mediated lipolysis was dependent on hormone-sensitive lipase and relied mechanistically on PKC zeta activation of MAPK to phosphorylate HSL at Ser660' (PMC11975168 — Intracellular Sphingosine-1-Phosphate Induces Lipolysis Through Direct Activation of Protein Kinase C Zeta). Ser660 is one of the two sites the epinephrine kinase uses. This is a separate road to the same switch. And here is why it is the safe road: the kinase family splits into three groups, and 'atypical aPKCs ARE unresponsive to DAG' — the very site that irritant plant compounds occupy (PMC6465381 — Differential Regulation... via Selective Activation of Protein Kinase C Isozymes). The compound class that causes the harm physically cannot activate this kinase. It is not a safer dose of the same thing; it is a different molecule entirely. In animals the effect is real but was produced by a drug: blocking the enzyme that destroys this messenger 'reduced white gonadal adipose tissue mass and diminished adipocyte size... and increased free fatty acid in plasma' — using a vitamin-B6 antagonist, which is not a food and carries its own problems. The route is proven; a safe botanical key for it is not yet identified. And it is a third road, not a branch of the first two: 'we observed NO inhibition of S1P-mediated lipolysis by the adenylate cyclase inhibitor SQ22536, whereas it completely inhibited isoproterenol-induced lipolysis. Inhibition of phosphatidylinositol 3-kinase had NO effect' (PMC11975168 — Intracellular S1P Induces Lipolysis Through Direct Activation of PKC Zeta). ⇒ this route uses neither of the two messengers the rest of this MAP runs on. And the action is inside the cell, not at its surface: '10-50 uM S1P potently increased lipolysis... Whereas S1P concentrations sufficient to activate S1P receptors (0.1-1 uM) OR S1PR agonists had NO effect.' Anything hoping to use this road has to get inside, which is a delivery problem nobody has solved for a swallowed ingredient. PMC11975168

Membrane lipid signaling increases it.

The second key is an ordinary membrane fat. 'PKC-zeta selectively binds phosphatidic acid (PA) and phosphatidylserine (PS) and weakly to phosphatidylglycerol' (doi 10.3390/biomedicines9010045 — Identification of Key Phospholipids That Bind and Activate Atypical PKCs). ⇒ the kinase that irritant plant compounds cannot touch is opened by two phospholipids that are already everyday supplement ingredients — both are already carried elsewhere in this catalog for entirely different purposes. Stated at its exact strength and NO further: this is a binding-and-activation finding on the kinase. It is not a fat-release experiment. Nobody has shown that swallowing either phospholipid releases fat in a person. What is shown is that the lock accepts this key, and separately that turning this lock releases fat. Nobody has yet turned it this way and measured the result. doi 10.3390/biomedicines9010045

Ceramide load increases it.

A dose that reverses itself, and it matters because another product in this range targets this molecule. 'low concentrations of ceramide were observed to transiently stimulate PKC zeta activity in vitro and in vivo, whereas high doses of ceramide lead to inhibition of PKC zeta' (PMID 10348660 — Atypical PKC zeta is activated by ceramide). ⇒ A little opens this kinase; a lot closes it. And the fat-release route does not run through ceramide at all: 'neither was ceramide increased by S1P, nor was S1P-mediated lipolysis affected by the ceramide synthase inhibitor FUMONISIN B1' (PMC11975168 — Intracellular S1P Induces Lipolysis Through Direct Activation of PKC Zeta). The two are neighbors in chemistry and separate in action. PMID 10348660 · PMC11975168

It increases Growth signal relay.

A second key that fits the same lock — and a lock the dangerous key cannot turn. 'S1P induced Thr410 phosphorylation of PKC zeta in 3T3-L1 adipocytes and activated recombinant PKC zeta in kinase assays. S1P-mediated lipolysis was dependent on hormone-sensitive lipase and relied mechanistically on PKC zeta activation of MAPK to phosphorylate HSL at Ser660' (PMC11975168 — Intracellular Sphingosine-1-Phosphate Induces Lipolysis Through Direct Activation of Protein Kinase C Zeta). Ser660 is one of the two sites the epinephrine kinase uses. This is a separate road to the same switch. And here is why it is the safe road: the kinase family splits into three groups, and 'atypical aPKCs ARE unresponsive to DAG' — the very site that irritant plant compounds occupy (PMC6465381 — Differential Regulation... via Selective Activation of Protein Kinase C Isozymes). The compound class that causes the harm physically cannot activate this kinase. It is not a safer dose of the same thing; it is a different molecule entirely. In animals the effect is real but was produced by a drug: blocking the enzyme that destroys this messenger 'reduced white gonadal adipose tissue mass and diminished adipocyte size... and increased free fatty acid in plasma' — using a vitamin-B6 antagonist, which is not a food and carries its own problems. The route is proven; a safe botanical key for it is not yet identified. PMC11975168

It increases Fat-releasing enzyme (HSL).

A second key that fits the same lock — and a lock the dangerous key cannot turn. 'S1P induced Thr410 phosphorylation of PKC zeta in 3T3-L1 adipocytes and activated recombinant PKC zeta in kinase assays. S1P-mediated lipolysis was dependent on hormone-sensitive lipase and relied mechanistically on PKC zeta activation of MAPK to phosphorylate HSL at Ser660' (PMC11975168 — Intracellular Sphingosine-1-Phosphate Induces Lipolysis Through Direct Activation of Protein Kinase C Zeta). Ser660 is one of the two sites the epinephrine kinase uses. This is a separate road to the same switch. And here is why it is the safe road: the kinase family splits into three groups, and 'atypical aPKCs ARE unresponsive to DAG' — the very site that irritant plant compounds occupy (PMC6465381 — Differential Regulation... via Selective Activation of Protein Kinase C Isozymes). The compound class that causes the harm physically cannot activate this kinase. It is not a safer dose of the same thing; it is a different molecule entirely. In animals the effect is real but was produced by a drug: blocking the enzyme that destroys this messenger 'reduced white gonadal adipose tissue mass and diminished adipocyte size... and increased free fatty acid in plasma' — using a vitamin-B6 antagonist, which is not a food and carries its own problems. The route is proven; a safe botanical key for it is not yet identified. PMC11975168