Phosphate
Inorganic Ions Metabolism

Author: Gianpiero Pescarmona
Date: 01/04/2008

Description

Phosphorus is an essential mineral that is required by every cell in the body for normal function

Avian multiple inositol polyphosphate phosphatase is an active phytase that can be engineered to help ameliorate the planet’s “phosphate crisis”

Effect of dietary phosphate

Factors affecting intestinal absorption

Factors affecting renal handling

Phosphatonins

Biological effects of FGF-23 and sFRP-4 on Na+-dependent Pi transport in Kidney cells (Role of PIPR sequence: arginine (I) is a Pin sensor?)

ref 2008

FGF-23 causes a redistribution and internalization of Na+-Pi IIa cotransporters on the surface of renal epithelial cells

Regulation of Fibroblast Growth Factor-23 Signaling by Klotho 2006

Ca P Klotho 2008

Mutations of the FGF23 gene found in patients with ADHR occur either in arginine176 or arginine179 just before the processing site of FGF23. Because these arginine residues are part of the arginine-X-X-arginine sequence recognized by furin-family endopeptidase, it was
anticipated that these mutations affect proteolytic processing of FGF23. Actually, when mutant FGF23 proteins found in patients with ADHR were expressed in vitro and analyzed by Western blotting, these proteins were shown to be resistant to the processing (REF 2005).

FGF-23(R176Q) suppressed 1alpha-hydroxylase mRNA and activated the ERK1/2 signaling pathway. The MAPK inhibitor PD98059 effectively abolished FGF-23-induced suppression of 1alpha-hydroxylase mRNA by blocking signal transduction via ERK1/2. REF 2007

Mechanism of action of sFRP-4. The secreted frizzled related proteins function as antagonists of the Wnt proteins. We demonstrated that the infusion of sFRP-4 into rats was associated with phosphaturia, a concomitant increase in the amount of phospho-β-catenin, and a decrease in the amount of nonphosphorylated β-catenin. Thus, sFRP-4 antagonizes Wnt signaling in the kidney. Infusion of sFRP-4 decreases Na+-Pi cotransporter abundance in the brush border membrane of the proximal tubule and reduced surface expression of the Na+-Pi IIa cotransporter in the proximal tubules

SFRP-4 abrogates Wnt-3a-induced beta-catenin and Akt/PKB signalling and reverses a Wnt-3a-imposed inhibition of in vitro mammary differentiation 2008

Papers FGF23 and VDR

Proteomic analysis of alterations in the secretome of Arabidopsis thaliana suspension cells subjected to nutritional phosphate deficiency 2008

Biochemistry. 2009 Aug 4;48(30):7140-9.
Succinyl-CoA synthetase is a phosphate target for the activation of mitochondrial metabolism. 2009

Phillips D, Aponte AM, French SA, Chess DJ, Balaban RS.

Succinyl-CoA synthetase (SCS) is the only mitochondrial enzyme capable of ATP production via substrate level phosphorylation in the absence of oxygen, but it also plays a key role in the citric acid cycle, ketone metabolism, and heme synthesis. Inorganic phosphate (P(i)) is a signaling molecule capable of activating oxidative phosphorylation at several sites, including NADH generation and as a substrate for ATP formation. In this study, it was shown that P(i) binds the porcine heart SCS alpha-subunit (SCSalpha) in a noncovalent manner and enhances its enzymatic activity, thereby providing a new target for P(i) activation in mitochondria. Coupling 32P labeling of intact mitochondria with SDS gel electrophoresis revealed that 32P labeling of SCSalpha was enhanced in substrate-depleted mitochondria. Using mitochondrial extracts and purified bacterial SCS (BSCS), we showed that this enhanced 32P labeling resulted from a simple binding of 32P, not covalent protein phosphorylation. The ability of SCSalpha to retain its 32P throughout the SDS denaturing gel process was unique over the entire mitochondrial proteome. In vitro studies also revealed a P(i)-induced activation of SCS activity by more than 2-fold when mitochondrial extracts and purified BSCS were incubated with millimolar concentrations of P(i). Since the level of 32P binding to SCSalpha was increased in substrate-depleted mitochondria, where the matrix P(i) concentration is increased, we conclude that SCS activation by P(i) binding represents another mitochondrial target for the P(i)-induced activation of oxidative phosphorylation and anaerobic ATP production in energy-limited mitochondria.

Comments
2009-04-12T17:37:50 - alessandra di liberto

Heparin binds to Fibroblast growth factors and potentiates the EGF-induced cells growth.

FGFs are key players in the processes of proliferation and differentiation of wide variety of cells and tissues.

This action of FGF23 could be involved in heparin-induced osteoporosis.

2008-11-28T13:45:53 - Gianpiero Pescarmona

Fosforemia predice calcio coronarico
I giovani adulti sano con elevati livelli ematici di fosforo hanno maggiori probabilità di presentare elevati livelli di calcio nelle coronarie rispetto agli altri. I livelli di fosforo sono correlati all'arteriosclerosi sia in modelli animali che nei pazienti con nefropatie avanzate, ma non era finora noto se questa correlazione sussistesse anche nei soggetti con funzionalità renale nella norma. I livelli di fosforemia sono un fattore di rischio di calcificazione coronarica anche se ancora all'interno del range di normalità: al di là dei fattori determinanti di base, ciò suggerisce che la fosforemia potrebbe essere utilizzata per identificare i giovani adulti i cui fattori di rischio modificabili dovrebbero essere controllati e gestiti in modo più aggressivo. (J Am Soc Nephrol online 2008, pubblicato il 5/11)

Perdita ossea e ponderale nel bypass gastrico
La densità ossea dell'anca declina in parallelo alla perdita di peso a seguito di un bypass gastrico: è alla perdita di peso che essa è correlata, piuttosto che a variazioni nel metabolismo del calcio o della vitamina D. Ciò conferma altri dati secondo cui la perdita di peso porta ad un declino della BMD, presumibilmente per via della diminuzione del carico meccanico osseo, anche se potrebbero essere coinvolti anche altri fattori. E' dunque estremamente importante che i medici che seguono questi pazienti valutino i livelli di vitamina D prima dell'intervento, provvedano a sanare ogni eventuale deficit e ripetano gli esami dopo l'intervento in modo da verificare che il regime applicato relativamente a calcio e vitamina D sia adeguato. Il pericolo di perdita d'osso comunque non deve frenare il desiderio del paziente di sottoporsi a chirurgia bariatrica, anche perché la maggior parte dei pazienti patologicamente obesi iniziano con una BMD molto elevata, e non giungono all'osteoporosi nemmeno dopo una certa perdita d'osso. Sono attualmente in corso alcuni studi per accertare se la perdita d'osso si stabilizza o meno una volta che il soggetto cessa di perdere peso, e determinare le cause dei deficit di vitamina D tanto comuni in questi pazienti. (J Clin Endocrinol Metab 2008; 93: 3735-40)

2008-06-25T12:34:59 - Gianpiero Pescarmona

Isocitrate dehydrogenase
Inhibition is achieved by an electrostatic blocking mechanism with no conformational changes, in which the serine-phosphate partially occupies the site recognized by the negatively charged substrate,
isocitrate, but does not make strong stabilizing interactions with positively charged residues in the vicinity.(Stroud RM: Mechanisms of biological control by phosphorylation. Curr Opin Struct Bio11991, 1:826-835.)

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