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Current Enzyme Inhibition
ISSN: 1573-4080
Current Enzyme Inhibition
Volume 3, Number 1, February 2007
Contents
MET and RON Receptor Tyrosine Kinases: Novel
Therapeutic Targets in Squamous Cell Carcinoma of the Head
and Neck Pp. 1-12
Susanne J. Rogers, Carol Box, Christopher M. Nutting,
, Kevin J. Harrington and Suzanne A. Eccles
[Abstract] [Full
text article]
Lysophospholipase D/Autotaxin in Lysophospholipid
Biology Pp. 13-17
Dong-Soon Im
[Abstract] [Full
text article]
Trypanosomatidae Peptidases: A Target for Drugs Development
Pp. 19-48
Alane Beatriz Vermelho, Salvatore Giovanni De Simone,
Claudia Masini d’Avila-Levy, André Luis Souza
do Santos, Ana Cristina Nogueira de Melo, Floriano Paes Silva
Jr., Elba Pinto da Silva Bon and Marta Helena Branquinha
[Abstract] [Full
text article]
Aldose Reductase in the Retina Pp. 49-60
Mahmoud Ahmed Mansour
[Abstract] [Full
text article]
Selective Inhibition of Animal DNA Polymerases by
Fat-Soluble Vitamins A, D, E and K and Their Related Compounds
Pp. 61-75
Yoshiyuki Mizushina, Yuko Yonezawa and Hiromi Yoshida
[Abstract] [Full
text article]
GHMP Kinases – Structures, Mechanisms and Potential
for Therapeutically Relevant Inhibition Pp. 77-94
David J. Timson
[Abstract] [Full
text article]
Abstracts
[Back to top]
MET and RON Receptor Tyrosine Kinases: Novel Therapeutic
Targets in Squamous Cell Carcinoma of the Head and Neck
Susanne J. Rogers, Carol Box, Christopher M. Nutting,
, Kevin J. Harrington and Suzanne A. Eccles
[Full
text article]
MET (hepatocyte growth factor receptor) and RON (recepteur
d’origine Nantaise) are members of the MET
proto-oncogene family of receptor tyrosine kinases (RTKs).
Signalling from MET or RON activates multiple signalling pathways
and ultimately promotes tumorigenesis and the formation of
metastases. Mutations in MET have been detected in
abundance in squamous cell carcinoma of the head and neck
(SCCHN) metastases relative to the primary tumour, suggesting
that this is a critical oncogene regulating dissemination.
The biological significance of RON in SCCHN is still relatively
unexplored. As survival has plateaued for patients with SCCHN,
novel therapies with effects on the primary tumour and metastatic
disease are urgently required. Small molecule inhibition of
MET has been achieved in the pre-clinical setting and future
clinical development is an exciting prospect. In this review,
we summarise the biology of MET and RON RTKs and their contribution
to an invasive tumour phenotype. We highlight their potential
as therapeutic targets and address putative roles for MET
and RON in resistance to conventional therapy, with particular
reference to SCCHN.
[Back to top]
Lysophospholipase D/Autotaxin in Lysophospholipid
Biology
Dong-Soon Im
[Full
text article]
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate
(S1P) are bioactive lysophospholipid mediators with a wide
variety of biological actions. G-protein-coupled receptors
for LPA and S1P have been identified, and physiological and
pathological significances of the lysophospholipids and their
receptors are under intensive investigation. Furthermore,
specific agonists and antagonists for the receptors have been
developed for clinical applications. However, mechanisms underlying
their production have not yet been fully elucidated. Recently,
autotaxin, an exo-phosphodiesterase implicated in tumor cell
migration, has been discovered as lysophospholipase D that
produces LPA and S1P from lysophosphatidylcholine and sphingosylphosphorylcholine,
respectively. In this article, I reviewed the structure, expression,
substrate specificity, enzymatic function, specific inhibitors
and pathophysiological significances of lysophospholipase
D/autotaxin.
[Back to top]
Trypanosomatidae Peptidases: A Target for Drugs
Development
Alane Beatriz Vermelho, Salvatore Giovanni De Simone,
Claudia Masini d’Avila-Levy, André Luis Souza
do Santos, Ana Cristina Nogueira de Melo, Floriano Paes Silva
Jr., Elba Pinto da Silva Bon and Marta Helena Branquinha
[Full
text article]
In most organisms around 2% of the genes code for peptidases
being this number only surmounted by the genes that code for
transcriptional factors. This ubiquitous presence is almost
unequaled and has for long fascinated biochemists. Although
peptidases have been classified in four mechanistic classes
(aspartic-, cysteine-, serine- and metallo-peptidases), the
more recent MEROPS database recognizes 42 evolutionary distinct
peptidase structures corresponding to 42 different families.
As peptidases are involved in several physiological processes
they are an obvious target for the development of therapeutic
agents to treat infectious disease. The Trypanosomatidae family
includes etiologic agents for human and veterinary diseases,
such as Trypanosoma cruzi, Leishmania spp. and the
African trypanosomes that are responsible for the Chagas disease,
for a wide spectrum of clinical manifestations known as leishmaniasis,
and for the “sleeping sickness”, respectively.
These microorganisms present a complex life cycle that includes
dimorphic developmental stages in distinct hosts and by extension
show nutritional adaptation. This review covers the recent
advances in the biochemical characterization of trypanosomatid
proteolytic enzymes and that of specific inhibitors to block
their hydrolytic activity, in accordance to the peptidases
potential role as target to the treatment of the aforementioned
illnesses.
[Back to top]
Aldose Reductase in the Retina
Mahmoud Ahmed Mansour
[Full
text article]
Aldose reductase (E.C. 1.1.1.21), an intracellular enzyme
of polyol pathway, catalyzes NADPH-dependent reduction of
glucose to sorbitol. Under normoglycemia, most of the cellular
glucose is phosphorylated into glucose-6-phosphate by hexokinase.
A minor part of non-phosphorylated glucose enters the polyol
pathway, the alternate route of glucose metabolism. However,
under hyperglycemia, because of saturation of hexokinase with
ambient glucose, aldose reductase is activated, leading to
excessive production of sorbitol. Intracellular accumulation
of sorbitol is thought to result in irreversible damage. In
the diabetic eye, the increased sorbitol accumulation in retina
has been implicated in the pathogenesis of retinopathy, characterized
by pericyte loss, basal membrane thickening, the major ocular
complications of diabetes. Nearly all diabetic subjects have
the same degree of retinopathy after 20 years of diabetes.
50% of patients with insulin dependent diabetes mellitus have
proliferative retinopathy after 15 years. In addition, macular
edema frequently produces central vision loss and blindness
most commonly in non-insulin dependent diabetes mellitus.
Therefore, aldose reductase enzyme inhibition is becoming
one of the therapeutic strategies that have been proposed
to prevent or ameliorate long-term diabetic complications.
[Back to top]
Selective Inhibition of Animal DNA Polymerases
by Fat-Soluble Vitamins A, D, E and K and Their Related Compounds
Yoshiyuki Mizushina, Yuko Yonezawa and Hiromi Yoshida
[Full
text article]
We found that fat-soluble vitamins (i.e., vitamins A,
D, E and K) have novel functions such as anti-cancer activity,
and we therefore investigated the inhibitory activity of DNA
polymerases (pols) from various species by vitamins and their
related compounds. In vitamin A-related compounds, fucoxanthin,
astaxanthin (provitamin A), all-trans retinal (vitamin
A aldehyde) and all-trans retinoic acid (vitamin
A acid) inhibited the activities of mammalian replicative
pols α,
δ and
ε with
IC50 values of 18-190, 14-17 and 8-30 μM,
respectively, and all-trans retinol (vitamin A) did
not influence any pol activities. In vitamin D-related compounds,
vitamins D2 and D3 were found to be
selective inhibitors of calf pol α
with IC50 values of 123 and 96 μM,
respectively, and provitamins D2, D3
and the active form of vitamin D3 such as 1α,
25-dihydroxyvitamin D3 could not influence any
pol activities. Tocotrienols, vitamin E compounds with an
unsaturated side chain with three double bonds, selectively
inhibited the activity of human pol λ
with IC50 values of 18-81 μM.
In vitamin K compounds, vitamin K3 selectively inhibited mitochondrial
pol γ
activity with an IC50 value of 6 μM,
although vitamins K1 and K2 did not
inhibit the activities of any pols. On the other hand, no
compounds tested influenced the activities of plant pols from
cauliflower, prokaryotic pols, or DNA metabolic enzymes tested.
These compounds suppressed the cell growth of a human gastric
cancer cell line, NUGC-3, and halted at the G1 phase in the
cell cycle. We discussed the molecular mechanism and relationship
between pol inhibitory activity and anti-cancer activity by
fat-soluble vitamins.
[Back to top]
GHMP Kinases – Structures, Mechanisms and
Potential for Therapeutically Relevant Inhibition
David J. Timson
[Full
text article]
The GHMP kinases are a structurally related family of
small molecule kinases named after four of its members –
galactokinase, homoserine kinase, mevalonate kinase and phosphomevalonate
kinase. The group also includes the enzymes N-acetylgalactosamine
kinase, arabinose kinase, mevalonate 5-diphosphate decarboxylase,
archeal shikimate kinase and 4-(cytidine 5'-diphospho)-2-c-methyl-D-erythritol
kinase. In addition the group includes two members not known
to be catalytically active, the Caenorhabditis elegans
sex-fate determining protein XOL-1 and the Saccharomyces
cerevisiae transcriptional activator Gal3p. Two catalytic
mechanisms have been proposed for GHMP kinases. The structure
of mevalonate kinase suggests that an aspartate residue acts
as an active site base, removing a proton from the substrate
to facilitate attack on the γ-phosphate
of MgATP. In contrast, in homoserine kinase there is no potential
catalytic base and it is proposed that catalysis is driven
by transition state stabilisation. Potential chemotherapeutic
interventions against GHMP kinases fall into three main categories:
inhibition of galactokinase to assist suffers of galactosemia,
inhibition of mevalonate kinase or mevalonate 5-diphosphate
decarboxylase to reduce flux through the cholesterol biosynthesis
pathway and inhibition of bacterial GHMP kinases for novel
anti-microbial therapies. These are in the early stages of
development, but the accumulation of structural and mechanistic
data will assist future progress.
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