Afonso de Albuquerque was born in 1453 in Alhandra, near Lisbon. He was the second son of Goncalo de Albuquerque, Lord of Vila Verde dos Francos, and Dona Leonor de Menezes. His father held an important position at court and was connected by remote illegitimate descent with the Portuguese monarchy. He was educated in mathematics and Latin at the court of Afonso V of Portugal, where he befriended Prince John, the future King John II of Portugal.

In December 1512 an envoy from Ethiopia arrived at Goa. Mateus was sent by the regent queen Eleni, following the arrival of the Portuguese from Socotra in 1507, as an ambassador for the king of Portugal in search of a coalition to help face growing Ottoman influence. He was received in Goa with great honour by Afonso, as a long-sought "Prester John" envoy. His arrival was announced by King Manuel to Pope Leo X in 1513. Although Mateus faced the distrust of Afonso's rivals, who tried to prove he was some impostor or Muslim spy, Afonso sent him to Portugal. The King is described as having wept with joy at their report. In February 1513, while Mateus was in Portugal, Afonso sailed to the Red Sea with a force of about 1000 Portuguese and 400 Malabaris. He was under orders to secure that channel for Portugal. Socotra had proved ineffective to control the Red Sea entrance and was abandoned, and Afonso's hint that Massawa could be a good Portuguese base might have been influenced by Mateus' reports. Knowing that the Mamluks were preparing a second fleet at Suez, he wanted to advance before reinforcements arrived in Aden, and accordingly laid siege to the city. Aden was a fortified city, but although he had scaling ladders they broke and after half a day of fierce battle Afonso was forced to retreat. He cruised the Red Sea inside the Bab al-Mandab, with the first European fleet to have sailed this route. He attempted to reach Jeddah, but the winds were unfavourable and so he sheltered at Kamaran island in May, until sickness among the men and lack of fresh water forced him to retreat. In August 1513, after a second attempt to reach Aden, he returned to India with no substantial results. In order to destroy the power of Egypt, he is said to have entertained the idea of diverting the course of the Nile river to render the whole country barren. Perhaps most tellingly, he intended to steal the body of the Islamic prophet, Muhammad, and hold it for ransom until all Muslims had left the Holy Land.

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