scholarly journals SLC1A5 provides glutamine and asparagine necessary for bone development in mice

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Deepika Sharma ◽  
Yilin Yu ◽  
Leyao Shen ◽  
Guo-Fang Zhang ◽  
Courtney M Karner

Osteoblast differentiation is sequentially characterized by high rates of proliferation followed by increased protein and matrix synthesis, processes that require substantial amino acid acquisition and production. How osteoblasts obtain or maintain intracellular amino acid production is poorly understood. Here we identify SLC1A5 as a critical amino acid transporter during bone development. Using a genetic and metabolomic approach, we show SLC1A5 acts cell autonomously to regulate protein synthesis and osteoblast differentiation. SLC1A5 provides both glutamine and asparagine which are essential for osteoblast differentiation. Mechanistically, glutamine and to a lesser extent asparagine support amino acid biosynthesis. Thus, osteoblasts depend on Slc1a5 to provide glutamine and asparagine, which are subsequently used to produce non-essential amino acids and support osteoblast differentiation and bone development.

2021 ◽  
Author(s):  
Deepika Sharma ◽  
Yilin Yu ◽  
Leyao Shen ◽  
Guo-Fang Zhang ◽  
Courtney M. Karner

Osteoblast differentiation is sequentially characterized by high rates of proliferation followed by increased protein and matrix synthesis, processes that require substantial amino acid acquisition and production. How osteoblasts obtain or maintain intracellular amino acid production is poorly understood. Here we identify Slc1a5 as a critical amino acid transporter during bone development. Using a genetic and metabolomic approach, we show Slc1a5 acts cell autonomously in osteoblasts to import glutamine and asparagine. Deleting Slc1a5 or reducing either glutamine or asparagine availability prevents protein synthesis and osteoblast differentiation. Mechanistically, glutamine and asparagine metabolism support amino acid biosynthesis. Thus, osteoblasts depend on Slc1a5 to provide glutamine and asparagine, which are subsequently used to produce non-essential amino acids and support osteoblast differentiation and bone development.


Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3267
Author(s):  
Martina Chiu ◽  
Denise Toscani ◽  
Valentina Marchica ◽  
Giuseppe Taurino ◽  
Federica Costa ◽  
...  

Multiple myeloma (MM) cells consume huge amounts of glutamine and, as a consequence, the amino acid concentration is lower-than-normal in the bone marrow (BM) of MM patients. Here we show that MM-dependent glutamine depletion induces glutamine synthetase in stromal cells, as demonstrated in BM biopsies of MM patients, and reproduced in vitro by co-culturing human mesenchymal stromal cells (MSCs) with MM cells. Moreover, glutamine depletion hinders osteoblast differentiation of MSCs, which is also severely blunted by the spent, low-glutamine medium of MM cells, and rescued by glutamine restitution. Glutaminase and the concentrative glutamine transporter SNAT2 are induced during osteoblastogenesis in vivo and in vitro, and both needed for MSCs differentiation, pointing to enhanced the requirement for the amino acid. Osteoblastogenesis also triggers the induction of glutamine-dependent asparagine synthetase (ASNS), and, among non-essential amino acids, asparagine rescues differentiation of glutamine-starved MSCs, by restoring the transcriptional profiles of differentiating MSCs altered by glutamine starvation. Thus, reduced asparagine availability provides a mechanistic link between MM-dependent Gln depletion in BM and impairment of osteoblast differentiation. Inhibition of Gln metabolism in MM cells and supplementation of asparagine to stromal cells may, therefore, constitute novel approaches to prevent osteolytic lesions in MM.


2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Ronald E. Viola ◽  
Christopher R. Faehnle ◽  
Julio Blanco ◽  
Roger A. Moore ◽  
Xuying Liu ◽  
...  

The aspartate pathway of amino acid biosynthesis is essential for all microbial life but is absent in mammals. Characterizing the enzyme-catalyzed reactions in this pathway can identify new protein targets for the development of antibiotics with unique modes of action. The enzyme aspartate β-semialdehyde dehydrogenase (ASADH) catalyzes an early branch point reaction in the aspartate pathway. Kinetic, mutagenic, and structural studies of ASADH from various microbial species have been used to elucidate mechanistic details and to identify essential amino acids involved in substrate binding, catalysis, and enzyme regulation. Important structural and functional differences have been found between ASADHs isolated from these bacterial and fungal organisms, opening the possibility for developing species-specific antimicrobial agents that target this family of enzymes.


2001 ◽  
Vol 43 (6) ◽  
pp. 383-390 ◽  
Author(s):  
Kibeom Lee ◽  
Jeewon Lee ◽  
Yang-Hoon Kim ◽  
Seung-Hyeon Moon ◽  
Young-Hoon Park

2022 ◽  
Author(s):  
Leyao Shen ◽  
Yilin Yu ◽  
Yunji Zhou ◽  
Shondra M Pruett-Miller ◽  
Guo-Fang Zhang ◽  
...  

Cellular differentiation is associated with the acquisition of a unique protein signature which is essential to attain the ultimate cellular function and activity of the differentiated cell. This is predicted to result in unique biosynthetic demands that arise during differentiation. Using a bioinformatic approach, we discovered osteoblast differentiation is associated with increased demand for the amino acid proline. When compared to other differentiated cells, osteoblast-associated proteins including RUNX2, OSX, OCN and COL1A1 are significantly enriched in proline. Using a genetic and metabolomic approach, we demonstrate that the neutral amino acid transporter SLC38A2 acts cell autonomously to provide proline to facilitate the efficient synthesis of proline-rich osteoblast proteins. Genetic ablation of SLC38A2 in osteoblasts limits both osteoblast differentiation and bone formation in mice. Mechanistically, proline is primarily incorporated into nascent protein with little metabolism observed. Collectively, these data highlight a requirement for proline in fulfilling the unique biosynthetic requirements that arise during osteoblast differentiation and bone formation.


2016 ◽  
Vol 6 (1) ◽  
pp. 846-852
Author(s):  
Olugbenga Adeniran Ogunwole ◽  
B. C Majekodunmi ◽  
R. A Faboyede ◽  
D. Ogunsiji

Effects of supplemental dietary lysine and methionine in a Groundnut Cake (GNC) based diets on meat and bone characteristics of broiler chickens were investigated. In a completely randomized design, a total of 168 one - day – old Arbor acre broiler chicks were randomly allocated to seven dietary treatments each in triplicate of eight birds per replicate. The Seven starter and finishers’ diets were: GNC based diets without any amino acid (lysine or methionine) supplementation (T1); GNC diet + 0.2% lysine (T2); GNC diet + 0.4% lysine (T3); GNC diet + 0.2% methionine (T4); GNC diet + 0.4% methionine (T5); GNC diet + 0.2 lysine and 0.2% methionine (T6) and GNC diet + 0.4% lysine and 0.4% methionine (T7). Experimental diets and water were offered to birds ad libitum in an experiment lasting six-week. At day 42, two birds per replicate were slaughtered, meat and bone characteristics determined. There were significant variations (P<0.05) in the crude protein (%) and ether extract (%), pH1 and pH2 of meat. Thiobarbituric acid reactive substances composition of meat at days 0, 5, and 10 were similar (P<0.05) and were not affected by dietary amino acid supplementation. Tibiotarsal index (mg/mm) of bone (22.10, 27.25, 33.35, 31.40, 28.70, 31.45 and 29.75 for broilers on T1, T2, T3, T4, T5, T6 and T7, respectively) were increased significantly (P<0.05) by amino acid supplementation. Significantly differences (P<0.05) were observed in the calcium, phosphorus and potassium (%) contents of broilers’ bone across treatments. Supplemental lysine and both lysine and methionine improved meat quality and bone development of broiler chickens in this study.


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