A novel approach to inhibit intracellular vitamin B₆‐dependent enzymes: proof of principle with human and plasmodium ornithine decarboxylase and human histidine decarboxylase

Abstract

Pyridoxal-5'-phosphate (vitamin B(6))-dependent enzymes play central roles in the metabolism of amino acids. Moreover, the synthesis of polyamines, which are essential for cell growth, and of biogenic amines, such as histamine and other signal transmitters, relies on these enzymes. Certain B(6) enzymes thus are prime targets for pharmacotherapeutic intervention. We have devised a novel, in principle generally applicable strategy for obtaining small-molecule cell-permeant inhibitors of specific B(6) enzymes. The imine adduct of pyridoxal-5'-phosphate and the specific amino acid substrate, the first intermediate in all pyridoxal-5'-phosphate-dependent reactions of amino acids, was reduced to a stable secondary amine. This coenzyme-substrate-conjugate was modified further to make it membrane-permeant and, guided by structure-based modeling, to boost its affinity to the apoform of the target enzyme. Inhibitors of this type effectively decreased the respective intracellular enzymatic activity (IC(50) in low micromolar range), providing lead compounds for inhibitors of human ornithine decarboxylase (hODC), plasmodium ornithine decarboxylase, and human histidine decarboxylase. The inhibitors of hODC interfere with the metabolism of polyamines and efficiently prevent the proliferation of tumor cell lines (IC(50)∼ 25 μM). This approach to specific inhibition of intracellular B(6) enzymes might be applied in a straightforward manner to other B(6) enzymes of emerging medicinal interest.

Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders

“…It is noteworthy that the irreversible inhibition of PLP (active form of vitamin B 6 ) has a range of potential undesirable and dangerous side effects due the interference with the activity of over 300 PLP-dependent enzymes and proteins [21]. It is not far from the reality to state that nearly every major biological system in the human body could be affected directly or indirectly by the inactivation of PLP which is needed in more than 140 different enzymatic pathways [22]. Carbidopa and benserazide are typical examples of drugs that permanently deactivate PLP by irreversibly binding to it.…”

Molecular characterization of novel pyridoxal‐5′‐phosphate‐dependent enzymes from the human microbiome

“…The structural and functional characterization of these novel PLPDEs paves the way for understanding their importance in symbiotic relationships of the human microbiome with the host in normal and disease states. Indeed, PLPDEs have been implicated in several diseases and have been explored in drug discovery . In addition, treatment with probiotics (gut microbiome bacteria) has also been shown to be useful in several therapies and offers advantages due to the nature of their symbiotic existence with the human host.…”

“…Indeed, PLPDEs have been implicated in several diseases and have been explored in drug discovery. [57][58][59][60][61] In addition, treatment with probiotics (gut microbiome bacteria) has also been shown to be useful in several therapies and offers advantages due to the nature of their symbiotic existence with the human host. Thus this exciting new area of research may prove to be a new frontier for design and application of novel therapeutics.…”

Biochemistry and Physiology of Vitamins in Euglena

“…The 5′-phosphate ester of pyridoxal, pyridoxal-5′-phosphate (PLP), is the co-enzyme form of vitamin B6 (Hellmann and Mooney 2010). Vitamin B6 enzymes synthesize, degrade, and interconvert amino acids and, thus, link nitrogen and carbon metabolism, replenish the pool of C1 units, and produce polyamines as well as important signaling molecules (Wu et al 2011). Pyridoxamine-5′-phospahte (PMP) and pyridoxine-5′-phoshate (PNP) are widely distributed in animal and plant cells (Sang et al 2007).…”